Methods, systems, and associated implantable devices for dynamic monitoring of physiological and biological properties of tumors

ABSTRACT

Methods of monitoring and evaluating the status of a tumor undergoing treatment includes monitoring in vivo at least one physiological parameter associated with a tumor in a subject undergoing treatment, transmitting data from an in situ located sensor to a receiver external of the subject, analyzing the transmitted data, repeating the monitoring and transmitting steps at sequential points in time and evaluating a treatment strategy. The method provides dynamic tracking of the monitored parameters over time. The method can also include identifying in a substantially real time manner when conditions are favorable for treatment and when conditions are unfavorable for treatment and can verify or quantify how much of a known drug dose or radiation dose was actually received at the tumor. The method can include remote transmission from a non-clinical site to allow oversight of the tumor&#39;s condition even during non-active treatment periods (in between active treatments). The disclosure also includes monitoring systems with in situ in vivo biocompatible sensors and telemetry based operations and related computer program products.

RELATED APPLICATIONS

This application claims priority from Provisional Application No.60/102,447 filed on Sep. 30, 1998. The contents of this application arehereby incorporated by reference herein.

FIELD OF THE INVENTION

This invention relates to diagnostic medical instruments and procedures,and more particularly to implantable devices and methods for monitoringphysiological parameters.

BACKGROUND OF THE INVENTION

The availability of a system and device capable of monitoring changeswithin any cell population of interest would be an important addition tothe cancer treatment armamentarium and one that will fill a need bymaking available more precise knowledge of the most sensitive time(s)for treating a tumor cell population. This vital information could aidin the delivery of highly specific individual treatment regime ratherthan the empirical and somewhat generalized treatment plans of today.

The in vitro study of malignant cell populations have establishedimportant general principles by which clinical treatment protocols aredeveloped. These principles have established differences betweenmalignant and normal cell populations and have been employed in thetreatment of malignant disease. There have been many attempts to exploitthese differences, both in pre-clinical and clinical studies, in orderto attempt to obtain total tumor cell kill and improved cure rates. Oneof the major obstacles in achieving this goal has been the difficulty inminimizing normal tissue toxicity while increasing tumor cell kill(therapeutic index). Thus, presently, most treatment strategies employan empirical approach in the treatment of malignant disease. That is,the timing of delivery and dose of cytotoxic agents are guided more bythe response and toxicity to normal tissue than by the effects on themalignant cell population. A major deficiency of this empirical approachis the lack of an efficient method or technique to provide accurateinformation on the dynamic changes during treatment (which can beextended over a long period of time) that occur within a malignant cellpopulation. Making this invaluable information available to attendingphysicians can allow clinicians to exploit the revealed differencesbetween malignant and normal cells, and hence improve the treatmentprocedures, to achieve better outcomes.

Much of the research in tumor biology has been involved in exploring thecellular, biochemical, and molecular difference between tumor and normalcells in order to improve the therapeutic index. Early cell kineticstudies revealed that cancer cells do not divide faster than normalcells, but rather a larger proportion of the cell population is dividing(Young et al., 1970). At that time, the failure to cure more tumors wasattributed to a variation in growth characteristics. In the 1980's, itwas proposed that these failures were due to development of resistanceof tumor cells through mutations of an unstable genome (Goldie et al.,1984). Later studies suggested that the mechanism for tumor cellsurvival rests on expression of a gene that codes for a specific proteinthat expels or extrudes the cytotoxic agents from the cell (Chaudhary etal., 1992). More recently, it has been suggested that resistance isrelated to dysregulation of the cell cycle which alters the rates ofcell growth (Lowe et al., 1994). Additional factors associated withfailure to eliminate or effect improved cure rate include hypoxic cellpopulations, cell proliferation variants, cell differentiation agents,and cell cycle sensitive stages. The ability to monitor these changesduring and following any treatment could offer a more precise knowledgeof the most sensitive portions of any cell population and aid in thedelivery of a more individualized and less empirical or generalizedtreatment program.

There have been a number of attempts to study certain of the dynamicchanges occurring within a cell population, but these attempts generallylack the ability to monitor the changes on a real time basis. Indeed,these methods typically provide information at one point in time andmost are designed to provide information on one particular function orparameter. In addition, most of the conventional methods can beexpensive as well as time consuming. This can be problematic forpatients undergoing extended treatment periods typical of radiation andor drug or chemotherapy, especially when it is desirable to followdynamic changes both during an active treatment and subsequent to theactive treatment throughout a treatment period.

The most reliable current monitoring technique is the biopsy. A biopsycan be taken at any time and can provide significant amount ofinformation. However, it is impractical to biopsy each day and, even ifone could, the time delay created in performing the various tests on thesample means that the information received by the physician is not anaccurate representation of the patient's current condition. In additionto biopsy material, the radiological techniques of NMR and PET scanningcan obtain, respectively, specific biological (cell cycle phase) andphysiological (phosphorus) information, but both are sufficientlyexpensive that repetitive or daily information is rarely available. Theradioactive labeling of specific antibodies or ligands is anotheravailable technique, but this method has many of the same problems notedabove with the other assays.

In addition, over time, tumors progress through periods wherein they areless robust and, thus, potentially more susceptible to treatment byradiation or drug therapy. Providing a monitoring system which cancontinuously or semi-continuously monitor and potentially identify sucha susceptible condition could provide welcome increases in tumordestruction rates. Further, especially for regionally targeted tumortreatment therapies, it can be difficult to ascertain whether thedesired dose was received at the tumor site, and if so received, it canbe difficult to assess its efficacy in a relatively non-invasive manner.Thus, there is a need for a monitoring system which can quantify and/orassess the localized or regional presence of a target drug.

Although much of the particular tumor-specific and/or internal systemicinformation which may definitively identify the most vulnerable tumorstage and, thus, the preferred active treatment period, is stillrelatively unsettled (as is the ultimate definitive cure or treatmentprotocol), various researchers have proposed several potentiallyimportant physiological and/or biological parameters such asoxygenation, pH, and cell proliferation which may relate to tumorvulnerability or susceptibility, and thus impact certain treatmentstrategies.

For example, in the article “Oxygen tension measurements of tumorsgrowing in mice,” it is proposed that it may be helpful to assesshypoxia in tumors during treatment. Adam et al., Int. J. RadiationOncology Biol. Phys., Vol. 45, 1998, pp. 171-180. In addition, tumorhypoxia has been proposed to have an impact on the effectiveness ofradiation therapy. See Seminars in Radiation Oncology, Vol. 8, 1998, pp.141-142. Similarly, the authors of “Development of targetinghyperthermia on prostatic carcinoma and the role of hyperthermia inclinical treatment” note that there is a need for a way to assesstemperature at the site of the tumor during therapy. Ueda et al., Jpn.J. Hyperthermic Oncol., Vol. 15 (supplement), 1999, pp. 18-19. Moreover,Robinson et al. opines that it is important to know the tumoroxygenation level and blood flow. See Robinson et al., “MRI techniquesfor monitoring changes in tumor oxygenation in blood flow,” Seminars inRadiation Oncology, Vol. 8, 1998, pp. 197-207. Unfortunately, tumoroxygenation can vary and there is evidence to suggest that tumoroxygenation is in a continuous state of flux. See Dewhirst, “Concepts ofoxygen transport at the microcirculatory level, ” Seminars in RadiationOncology, Vol. 8, 1998, pp. 143-150. This flux makes a dynamicmonitoring method important for identifying when the tumor oxygenationlevel is such that a more active treatment strategy may be desired. Inaddition, tumor pH has been suggested as an exploitable parameter fordrug design for tumor treatments. See Leo E. Gerweck, “Tumor pH:Implications for Treatment and Novel Drug Design”, 8 Seminars inRadiation Oncology No. 5, pp. 176-182 (July 1998).

In the past, various biotelemetry devices and implantable sensors havebeen proposed to monitor cardiac conditions or physiological parametersassociated with glucose or temperature. For example, U.S. Pat. No.5,791,344 to Schulman et al. entitled “Patient Monitoring System,”proposes a system to monitor the concentration of a substance in asubject's blood wherein one enzymatic sensor is inserted into a patientto monitor glucose and then deliver insulin in response thereto.Similarly, PCT US98 05965 to Schulman et al, entitled “System ofImplantable Devices for Monitoring or Affecting Body Parameters,”proposes using microsensors and/or microstimulators to sense glucoselevel, O₂ content, temperature, etc. There are also a number ofimplantable medical devices and systems which monitor physiological dataassociated with the heart via telemetry. One example of this type ofdevice is described in U.S. Pat. No. 5,720,771 to Snell entitled,“Method and Apparatus for Monitoring Physiological Data From anImplantable Medical Device.” The contents of these applications arehereby incorporated by reference as if recited in full herein.

In addition, unlike conventional implanted sensors, tumor monitoringsystems and/or sensors used to monitor tumors can be exposed to arelatively harsh environment during a treatment protocol or strategywhich can extend over a period of weeks, or even months (such as appliedheat, chemicals and/or radiation). Further, such a harsh environment,coupled with an extended treatment period, can affect the function ofthe device and thus, potentially corrupt the measurement data itgenerates.

In view of the foregoing, there remains a need for tumor monitoringsystems and devices which can, inter alia, monitor the physiologicaland/or biological condition of a tumor during a treatment cycle toidentify enhanced or favorable treatment windows to potentially increasein vivo treatment efficacy associated with such treatment.

OBJECTS AND SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide monitoringsystems, methods, and associated devices which can dynamically monitormultiple tumor physiological and biological parameters and/or changesassociated with tumors to identify enhanced or favorable treatmentconditions to thereby establish a patient-specific treatment deliverytime.

It is also an object of the present invention to provide a dynamicand/or semi-continuous (or even substantially continuous) tumormonitoring system which can be remotely monitored on an ongoing basisduring treatment.

It is an additional object of the present invention to provide animplantable cancerous tumor sensor system which is cost-effective andwhich can provide sufficient ongoing, and preferably substantiallyreal-time, information pertaining to the physiological and/or biologicalcondition of the tumor during a treatment period in a way which providesthe information to the physician to assist in therapeutic decisions.

It is yet another object of the present invention to provide a tumormonitoring system which can provide real-time information regardingcancerous tumor physiology as an adjunct to therapy.

It is an additional object of the present invention to provide acancerous tumor monitoring system which can provide clinically effectiveregionally specific data representative of the dynamic effects ofcytotoxic agents on cell populations during an extended treatmentperiod.

It is another object of the present invention to provide an implantableoxygen sensor configuration which is particularly suitable formonitoring the oxygenation and/or pH level in a tumor.

It is yet another object of the present invention to provide systemrelated sensors and computer program products for identifying when atumor exhibits potential vulnerability or susceptibility based on dataassociated with an in vivo in situ sensor which provides measurements ofparameters associated with a tumor.

It is another object of the present invention to provide a method ofremotely monitoring parameters associated with a patient's canceroustumor physiology and alerting a clinician of the presence of a conditionindicating a favorable treatment period or the need for other evaluationor adjustment in an ongoing planned treatment strategy.

It is an additional object of the present invention to provide a systemfor monitoring tumors which can indicate (in substantially real time)whether conditions are favorable or unfavorable for an active treatmentsuch as drug delivery, hyperthermia, chemotherapy, or radiation therapy.

It is still another object of the present invention to provide a systemor computer program product for analyzing a plurality of measurementsgenerated by at least one implanted sensor and analyzing themeasurements and identifying the presence or absence of one or morepredetermined conditions associated with the measurements to alert theclinician of the existence of a potentially vulnerable and desiredtreatment phase for a tumor.

These and other objects of the present invention are provided by abio-telemetry based tumor monitoring system with in vivo, in situsensors positioned to monitor multiple selected parametersrepresentative of the status of a tumor or tumors in a subject.

More particularly, a first aspect of the present invention is a methodof monitoring and evaluating the status of a tumor undergoing treatment.The method includes the steps of monitoring in vivo at least onephysiological parameter associated with a tumor in a subject undergoingtreatment with an in situ sensor. Data associated with at least onemonitored physiological parameter is transmitted from an in situpositioned sensor to a receiver external of the subject. The transmitteddata is analyzed to determine how the tumor is responding to treatment.Additional data is transmitted and analyzed periodically at a pluralityof sequential points in time, and a tumor treatment strategy isevaluated based on the analyzing step.

In a preferred embodiment, the transmitting and analyzing steps arerepeated sufficiently often (such as at least every 24 hours, and morepreferably at least hourly, at least during particular time segments oftreatment) to track variation in at least one monitored parameter andthereby assess the behavior of the tumor over time. It is also preferredthat at least one parameter is a plurality of parameters, and that theanalyzing step defines a plurality of test conditions associated withthe monitored parameters to evaluate the treatment corresponding to thecondition of the tumor (such as the efficacy of treatment or thepresence or absence of favorable indices of treatment). If thetransmitted data satisfies at least one test condition related to themonitored physiological parameters, a clinician can then be alerted asto the presence of at least one of a favorable and unfavorable treatmentwindow for delivering a subsequent active treatment to the tumor.Preferably, the favorable treatment window corresponds to theidentification of a tumor susceptibility or vulnerability phase.

It is also preferred that the transmitting step comprises transmittingdata from the home site of the patient to a remote clinical site therebyallowing real-time remote dynamic monitoring of the physiologicalparameter. Further, it is also preferred that the transmitting step isrepeated temporally proximate to a subsequent active treatment deliverytime to provide real-time information regarding the desirability of thetiming of a planned treatment or the efficacy of a delivered treatment.

Another aspect of the present invention is directed to a tumormonitoring system for evaluating the efficacy of radiation or drugtreatment and/or identifying enhanced or favorable active treatmentwindows. The system comprises at least one sensor unit comprising aplurality of sensor elements and associated sensor electronicsconfigured for in vivo, in situ contact with a cancerous tumor in asubject undergoing treatment. The sensor elements are configured tosense a plurality of different physiological parameters associated withthe tumor and wirelessly transmit the sensed data. The sensor units havean implanted service life of at least about 6-10 weeks, and morepreferably at least about 8-12 weeks. The system also includes a remotereceiver in wireless communication with the at least one sensor unit,and is configured to receive the transmitted sensor data. The receiveris positioned external to the subject.

The system also preferably includes a data processor configured toreceive the transmitted data including computer program code means forreviewing and adjusting the received data to correct for variationsattributed to environmental exposure in the subject.

An additional aspect of the present invention is directed to a computerprogram product for monitoring and analyzing the condition of a tumorundergoing treatment. The computer program product comprises a computerreadable storage medium having computer readable program code meansembodied in the medium. The computer-readable program code meanscomprises computer readable program code means for commencing a firstwireless data transmission from an in situ sensor with at least onesensor element, where the at least one sensor element is positioned in asubject proximate to a tumor undergoing treatment to monitor at leastone physiological or biological parameter of the tumor, and the datatransmission includes data corresponding to the output of the at leastone sensor element. The product also includes computer readable programcode means for commencing a second wireless data transmission from thein situ sensor temporally separate from the first wireless datatransmission and computer readable program code means for trackingvariation between the first and second data transmissions to provide adynamic behavioral model of the tumor's response to the treatment.

Preferably, the computer program product further comprises computerreadable program code means to evaluate the efficacy of the treatmentcorresponding to either of a predetermined absolute value or relativechange of the monitored at least one physiological parameter over time.It is also preferred that the computer program product further comprisescomputer readable program code means for commencing ongoing periodicdata transmissions over a predetermined (and/or adaptively determined orscheduled) time period, and computer readable program code means foranalyzing the data transmissions to identify potential enhanced orfavorable active treatment opportunities.

Advantageously, and in contrast to the empirical treatment strategiesemployed in the past to schedule active treatments (such as chemotherapyor radiation therapy), the present invention now allows targeted tumortreatment directed by the response or behavior of the malignant cells ofa tumor itself as well as the response of the normal cells proximate tothe tumor(s). Further, the present invention allows both real-timetreatment information during active therapy sessions as well as dynamictracking during non-active periods. Indeed, a patient can transmit orcommunicate the monitored parameters on a regular basis with a clinicalsite via implantable telemetry based sensing devices and home basereceivers (such as even multiple times in a 24 hour period) in arelatively cost-efficient manner. This ongoing communication candownload real-time information regarding the state of the tumor to aclinical monitoring station. This information can then be analyzed bycomputer programs to identify or evaluate oncology treatment strategiesassociated with a particular tumor type. For example, the dynamictracking can identify relative changes in the tumor and/or absolutevalues associated with a positive or negative reaction to therapy. Thisreaction tracking can allow for more proactive therapeutic decisionsbased on the tumor's response to the treatment. The dynamic tracking canalso be used to identify the onset or predict a potentially vulnerablephase of a tumor to allow more effective timing of treatment regimescorresponding to the actual behavior of the tumor. Preferably, thesensors are positioned at more than one location in the tumor (surfaceand at a penetration depth), and more preferably at more than one region(over the volume or surface area) associated with the tumor(s) to beable to quantify the tumor's overall response to therapy.

Advantageously, the systems, methods, and devices of the presentinvention can monitor, in real time and/or dynamically, specific indicesassociated with tumor physiology making them available for immediate usein treatment decisions. Hence, the instant invention can lead to moredefinitive and patient-specific treatment protocols, increase tumorresponse, decrease treatment morbidity, and improve and/or replaceassays predicting tumor response, resistance and sensitivity. Thepresent invention can provide information not previously readilyavailable for commercial clinical applications which will likely opennew fields of research and therapeutics. The device is particularlysuitable for oncology applications.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic illustration of a tumor monitoring systemaccording to the present invention. The illustration portrays areal-time monitoring capability.

FIG. 1B is a schematic illustration of an alternate tumor monitoringsystem according to the present invention. This figure illustrates anongoing dynamic remote monitoring capability.

FIG. 2A is a schematic diagram of a tumor monitoring system configuredto relay real time tumor information during an active treatment session(shown as an electric field treatment therapy) according to oneembodiment of the present invention.

FIG. 2B is a block diagram illustrating a tumor monitoring systemconfigured to relay information (real-time) during a hyperthermia andradiation treatment session.

FIG. 3 is a block diagram of a method of monitoring a tumor undergoingtreatment according to the present invention.

FIG. 4 is a flow chart of a method to identify favorable and unfavorabletreatment times according to the periodic (dynamic) monitoring of aplurality of tumor physiological parameters according to the presentinvention.

FIG. 5 is a top view of an implantable biocompatible sensor according tothe present invention.

FIG. 6A is a top view of an alternative implantable biocompatible sensoraccording to the present invention.

FIG. 6B is a side view of the sensor shown in FIG. 6A.

FIG. 7 is a side section view of an injectable microsensor according tothe present invention.

FIG. 8A is a section view of the sensor shown in FIG. 7 taken along line8A—8A.

FIG. 8B is a front perspective view of an alternative embodiment of aninjectable microsensor similar to the embodiment shown in FIG. 7.

FIG. 9 is a schematic illustration of an implant sensor according toanother embodiment of the present invention.

FIG. 10A is a greatly enlarged cutaway front view of a mock implant of apH sensor with a pH (ionophore) membrane according to the presentinvention.

FIG. 10B is a side view of an alternate embodiment of a pH sensor (withiridium oxide).

FIG. 11 is a schematic illustration of an experimental setup used toevaluate an implant tumor sensor according to the present invention.

FIG. 12 is a block diagram of a circuit for an implantable sensoraccording to the present invention.

FIG. 13 is a graph of the operation of an exemplary transmitteraccording to the present invention.

FIGS. 14A-C are graphs illustrating transmitter operational parametersaccording to one embodiment of the present invention. FIG. 14Aillustrates capacitor voltage over time, FIG. 14B illustrates controlvoltage over time, and FIG. 14C illustrates an output voltage waveform.

FIG. 15 illustrates an IC block diagram according to one embodiment ofthe present invention.

FIG. 16 is a pictorial representation of an IC layout corresponding toFIG. 15.

FIGS. 17A and 17B are graphs of the results of IC prototype temperatureexperiments. FIG. 17A illustrates temperature versus pulse width of datacorresponding to a thermistor (with the chip inside a water bath ofvarying temperature). FIG. 17B illustrates temperature versus pulsewidth of data corresponding to a fixed resistor (also with the chipinside a water bath of varying temperature).

FIGS. 18A and 18B are graphs of the results of IC prototype radiationexperiments. FIG. 18A illustrates pulse width versus radiation of datacorresponding to the thermistor with the chip inside the water bath andexposed to radiation from about 0-8000 cGray (a patient is typicallytreated with radiation in the range of about 3000-6000 cGray). FIG. 18Billustrates the data corresponding to the fixed resistor data with thechip inside the water bath and exposed to radiation from about 0-8000cGray.

FIG. 19A is a schematic illustration of a subject with monitoring systemwith two separate and spaced apart implant sensors positioned on twodifferent tumors according to one embodiment of the present invention.The monitoring system receiver can refocus to monitor both locations andtransmit the data to a remote location.

FIG. 19B illustrates an implant sensor with four sensor elements inposition (in situ in vivo) according to one embodiment of the presentinvention. As shown, two of the sensor elements are positioned atdifferent surface locations on the tumor, while one of the sensorelements is positioned to penetrate a depth into the tumor. Stillanother of the sensor elements is positioned proximate to normal tissuethat is proximate to the malignant tissue or tumor.

FIG. 20 is a schematic illustration of a self-calibrating in situ, invivo microsensor.

FIG. 21 is a photograph of a self-calibrating oxygen sensor.

FIG. 22 is a section view of a self-calibrating combination pH and O₂sensor.

FIGS. 23A-23C are side views of the sensor of FIG. 22 illustrating afabrication sequence.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention now will be described more fully hereinafter withreference to the accompanying drawings, in which preferred embodimentsof the invention are shown. This invention may, however, be embodied inmany different forms and should not be construed as limited to theembodiments set forth herein; rather, these embodiments are provided sothat this disclosure will be thorough and complete, and will fullyconvey the scope of the invention to those skilled in the art. Likenumbers refer to like elements throughout. In the figures, certainlayers, regions, or components may be exaggerated or enlarged forclarity.

Generally stated, the systems, devices, and methods of the presentinvention are aimed at monitoring the changes in physiology and kineticsof living systems. More specifically, the present invention's goal is tomonitor at sufficient intervals (preferably semi-continuously, and morepreferably substantially continuously) the changes in oxygen, pH, andcell proliferation of any organ or tumor system under “normal”physiological conditions, in-situ, as well as prior to, during andfollowing any perturbation (such as radiation, chemical or cytotoxicstimuli and hyperthermia) of such systems. As such, the monitoringsystems and methods of the present invention can be useful in manyapplications, such as, for example, pulmonary, gastrointestinal,neuroscience and pre-clinical research. Nonetheless, the presentinvention has a particular importance and suitability to tumor systems.As such, the following description of preferred embodiments willprimarily discuss the utilization of the present invention for cancerapplications.

As noted above in the Background of the Invention, most conventionalcancer treatment strategies employ an empirical approach. That is, thetiming and delivery of cytotoxic agents are guided more by the responseand toxicity to normal tissue than by the effects on the malignant cellpopulation. Thus, a major deficiency of this empirical approach is thelack of an efficient method or technique to provide accurate informationon the dynamic changes during treatment that occurs within a malignantcell population. Making this invaluable information available toattending physicians will allow them to exploit the revealed differencesbetween malignant and normal cells, and hence improve the treatmentprocedures to achieve better outcomes. Conventionally, the normal tissuesurrounding the tumor governs the dose of radiation and the schedulingand doses of chemotherapy is most dependent on the tolerance of thepatient's bone marrow. The primary reason for the lack ofindividualization of treatment is that there is presently nocommercially viable means by which the basic information on kinetics andphysiology of the tumor can be obtained during and following treatment.A biopsy of the tumor will yield information at one point in time andtherefore is valid for only that point in time. This static “snapshot”information may not be valid for predicting the cell kinetics,especially cell kinetics following perturbation by any cytotoxic agent.

There have been a number of attempts to study the dynamic changesoccurring within a cell population. However, these lack the ability tomonitor the changes on a real time basis. Instead, the conventionalmethods provide information at one point in time, most are designed toprovide information on one function, and most are expensive and timeconsuming, especially when one considers that it is important to monitorparameters before, during, and following treatment.

The major goal of cancer therapy is to eliminate all tumor cells.Knowledge of the specific change occurring within the tumor atsubstantially any time can be desirable in order to achieve maximumtumor cell kill and minimum normal tissue damage. Cytotoxic agents aremost effective at specific times and conditions of tumor growth. If themost vulnerable time of the tumor cells can be determined, i.e., thetime of maximum oxygenation or identification of an increase in cellproliferation associated with phases of the cell cycle, then thisinformation can be used to direct the time of delivery and the choice ofthe cytotoxic agents.

Preclinical and clinical medicine are in need of information on thedynamic changes which occur in malignant tissue prior to, during, andfollowing cytotoxic (active) therapy sessions in order to define moreclearly the circumstances for increasing tumor response. Access to suchinformation can allow for more precise timing of the delivery ofcytotoxic agents as well as identifying the most appropriate agent(s),e.g., radiation or chemotherapy therapy. Conventional radiologicalinvestigations are limited by their ability to observe dynamic changes,although NMR and PET scan can identify some functional changes. Thecurrently available anticancer agents, although effective in a limitednumber of tumors, are relatively ineffective in the majority of cancers.The instant invention recognizes that the reasons for this lack ofimprovement in outcome are typically multifactorial and related in partto an inability to measure, in situ, the time profiles of the mostsensitive parameters. These tumor parameters include one or more of, butare not limited to, the degree of oxygenation, pH, cell cycle phases,cell proliferation, and the molecular and cellular determinants ofsensitivity or resistance to cytotoxic agents. The present inventionrecognizes that the availability of such information and the ability toact upon such information can provide the means of overcoming a majorbarrier to improvements in outcome in cancer therapy. Further, it isbelieved that this newly provided information can create a shift in thetherapeutic paradigm from empirical to individual based therapy whichcan rely (at least in part) on the molecular and cellular properties ofthe individual patient's tumor.

Advantageously, the present invention now can provide information on thechanges occurring during and after therapy which can be utilized todirect therapy and/or to monitor the effects of the therapy. Thisindividualization of therapy can not only improve outcome but alsodecrease toxicity and morbidity of the treatment. That is, theinformation obtained on each patient's tumor can radically change thescheduling of therapy and result in an improved outcome. For example,patients can now be monitored from home, through telephone lines or someother remote interface, to determine a favorable or most appropriatetime for treatment.

Thus, as noted above, the present invention is primarily directed to thein vivo evaluation and monitoring of tumors prior to, during, andsubsequent to an active treatment, and preferably over an entiretreatment regime or period. That is, the present invention isparticularly suitable for monitoring the behavior of cancerous tumorssuch as sarcomas and carcinomas over a particular non-remissiontreatment period. As such, the internal in situ sensors of the presentinvention are preferably configured to be biocompatible and provide aservice life suitable for episodic treatment evaluation of at leastabout 4-6 weeks, and more preferably at least about 6-10 weeks, andstill more preferably at least about 10-12 weeks, whether exposed toradiation, chemotherapy, heat or ionic electric fields (such as thetreatment provided by a Thermotron®) directed to the tumor. The sensorsand preferred tumor monitoring parameters will be discussed furtherbelow.

Turning now to FIG. 1A, a real-time tumor monitoring system 10 isillustrated. As shown, the tumor monitoring system 10 includes an insitu sensor unit 50 positioned in a subject 20 proximate to a tumor 25.Preferably, as is also shown, the sensor unit 50 includes a plurality ofsensor elements 51 positioned at different locations on and/or into thetumor 25. It is preferred that the sensor elements 51 monitor more thanone physiological parameter or a selected physiological parameterassociated with the tumor at more than one position in, on, or about thetumor as will be discussed further below. The sensor unit 50 isconfigured with a telemetry link 60 to wirelessly communicate with anexternally located receiver 75. The receiver 75 includes a computerinterface 76 and is operably associated with a physician interfacemodule 80 such as a display monitor associated with a central processingunit, computer, or other computer means to allow physician access to themonitored data. As shown, the physician interface 80 is a laptop orother mobile/portable computer means to allow a physician instant accessto the substantially real-time monitored tumor parameters.

FIGS. 2A and 2B illustrate exemplary applications of real-timeevaluations according to the present invention. FIG. 2A illustratesusing the monitored parameter(s) of the tumor during a hyperthermiatherapy session (such as via Thermotron® device) to control the length,power, field strength, or polarity of the treatment. This control can beprovided because the real-time monitored data associated with at leastone tumor parameter can provide feedback on the actual treatmentpenetration depth (via temperature or other parameter) at the tumoritself. Alternatively, the information regarding the condition orbehavior of the tumor may suggest another treatment would be morebeneficial, or even that further treatment would not be beneficial (atthat time). Indeed, it is preferred that prior to initiation of anyactive treatment, the tumor data is monitored to assess whetherconditions are favorable or indeed, unfavorable, for the treatmentstrategy proposed. That is, if a drug therapy is recommended for tumorsexhibiting a pH above a certain value, and the data suggests that thetumor pH is below this value, a physician may choose to postpone thatparticular therapy for a more favorable time. Of course, otherparameters, such as an elevated oxygenation level and a phase ofincreased cell proliferation, may suggest that other therapy would bemore advantageous or that the drug therapy should nonetheless proceed.Additional discussion regarding tumor parameters and the relationship totreatment is provided below.

FIG. 2B illustrates the use of the real-time tumor data in a controlfeedback loop to control one or more of the power, dose, or duration ofa hyperthermia and radiation treatment session. As shown the monitoredtransmitted data is sent to the receiver, 75 which then inputs the datainto a computer which has a controller directing the actuator 92 andtreatment source 91 (which directs the treatment into the patient). Thepatient 20 is noted as the controlled “plant” in this figure.

FIG. 1B illustrates an alternate embodiment of a tumor monitoring system10′. In this embodiment, the tumor monitoring system 10′ includes a homereceiver unit 75′ and a remote interface 78 which communicates with thephysician interface 80 (the physician interface shown in this embodimentis a central processing unit). The patient 20 (the dotted linerepresents the patient being in the house proximate to the receiver 75′)even when at home can continue to monitor and transmit data to a remotesite. The remote interface 78 can provide the communications linkbetween the monitored local data and a remote clinical oversightstation. As such, the remote interface 78 can be provided by any numberof interface or data load means including a computer modem, a wirelesscommunication system, an internet connection, or telephone connection.In this embodiment, upon identification of the existence or onset of afavorable condition for treatment, the central processing site canautomatically schedule an evaluation appointment or even schedule atreatment session on therapeutic equipment to take advantage of anopportune or favorable treatment window(s).

FIG. 3 illustrates a preferred tumor monitoring and treatment evaluationmethod according to the present invention. At least one (and preferablya plurality of) physiological parameter associated with a tumor in asubject undergoing treatment is monitored (Block 100). Data associatedwith the at least one physiological parameter is transmitted from an insitu positioned sensor unit 50 to a receiver 75 located external to asubject (Block 110). The data transmission can be remotely transmittedfrom a non-clinical site (such as at a patient's home) to a clinicalsite via modem, telephone, wireless communication systems, and the like(Block 115). The transmitted data is then analyzed to determine acondition of the tumor (Block 120). The monitoring, transmitting, andanalyzing steps are repeated at a plurality of sequential points in time(Block 125). That is, as opposed to a “static” single point in time datapoint, the instant invention allows dynamic monitoring (a plurality ofsequential points in time). The dynamic tracking to variation in thetumor can yield valuable therapeutic and diagnostic information. Thedata is transmitted on a periodic basis (such as every 4-24 hours) overa particular treatment period. The data is transmitted in an at least anintermittent manner (although the data may be transmitted in less ormore frequent data transmissions) during an entire treatment cycle,typically from about 1-3 months. More preferably, the data issubstantially continuously or semi-continuously monitored (every 1-60minutes, and more preferably every 1-30 minutes) and, at least locally,transmitted. This ongoing (intermittent, semicontinuous, orsubstantially continuous) monitoring allows the dynamic tracking ormonitoring of the physiological parameter(s).

Of course, the continuous or semi-continuous monitoring/transmitting canbe performed locally for electronic storage within memory associatedwith the receiver/computer interface 75′ and then subsequentlytransmitted (to a central monitoring site on a less frequent basis, suchas hourly, daily, and the like). It may be beneficial to preset a datatransmittal/acquisition time via a timer in communication with thereceiver 75′ corresponding to a physician's input (e.g., more frequentmonitoring closer in time to the introduction of cytoxic agents orpertubation, such as every 1-5 minutes, with less frequent monitoringsubsequent thereto, such as every 10-15 minutes, or hourly).Alternatively, the data monitoring/transmitting or acquisition time maybe self-adjusting and relatively set such as by comparing and reviewingthe transmitted data periodically to determine rates of change uponwhich to institute a more frequent assessment, then transmit lessfrequently during times of less change in the values. In any event, forstationary receiver units 75, 75′, the patient needs to be in proximateposition with the receiver 75′ to facilitate proper data transmittal. Inorder to facilitate the proper position of the patient for a subsequenttransmittal to the receiver 75′, the receiver 75′ is preferablyconfigured to generate an alert or alarm when a desired monitoringtransmittal time is approaching. This can remind a subject to approachthe receiver for proper transmission therebetween. Of course, thereceiver 75′ can be programmed to audibly state the next transmittingtime based on the values of the most recently transmitted data while themore current transmittal is still underway (or on the change between aseries of more recent transmittals).

In an alternative embodiment to the home-based tumor monitoring system10′ shown in FIG. 1B, the receiver 75′ can be configured to be portableand sufficiently, light weight to allow a user to wear it (attached toclothing or other supporting belts or suspenders or the like) such thatit is in a desired proximity to the imbedded sensor unit(s) 50 to moreeasily provide semi-continuous or substantially continuous dynamic datatracking. Preferably, the portable receiver unit (not shown) isself-powered with a trickle charger (to plug into a vehicle accessorypower source or a wall outlet in the home) to allow a user to rechargethe unit when not mobile. It is also preferred that the portable unit beconfigured with sufficient memory to be able to store a block of dataover a period of time before uploading to the remote interface, ordirectly to a computer interface at a clinical site.

In any event, referring again to FIG. 3, a tumor treatment strategy canbe evaluated based on the dynamic information provided by the monitoredparameter(s) (Block 130). This evaluation can result in a verificationof the efficacy of a treatment (Block 132) such as, for example, todetermine whether the tumor is responding or resistant to the treatment.Further, the evaluation can verify that a given active dose was receivedat the.tumor and in what amount. One example is to quantify the amountof radiation seen or received at the tumor (this can be helpful if thetumor is blocked by dense tissue or is irregularly configured orpositioned in the body in hard to reach regions). This verification mayalso be particularly suitable for use with newer targeted drugs whichare designed to target the specific treatment zone in the body. Thisverification can thus affirm that the drug is delivered to the regionintended.

In addition, the evaluation can be advantageously used to identifyeither, or both, of the presence of a favorable or unfavorable treatmenttime (Block 134). For example, if conditions indicate the tumor is notreceptive to the planned treatment, a change in the planned therapy canbe promptly instituted, or, in the reverse, the resistance can result ina rescheduling of a planned therapy to a more favorable time, therebyminimizing exposing the subject to unnecessary therapy sessions atunfavorable times. In addition, the therapeutic evaluation can be basedon either or both of relative or absolute parameter values (or indeed aclustering of irregular, positive, or negative parameter values) todetermine if the treatment is progressing according to a predictivemodel. The predictive model can be based on the deviation of the tumor'sresponse to the delivered therapy at a particular point in time asmeasured against a population norm or even against a historicalperspective of the patient's own responses to previously deliveredtherapies. This can allow a physician to choose (or modify) the therapyfor a subject based on the responsiveness of the tumor itself. Thus, theinformation can result in modification of the planned treatment regime(Block 136). For example, for discussion purposes, assume that at Day 3from a chemotherapy type and dose, the tumor oxygenation is low, and thenormal cell's susceptibility to toxic agents is high. In contrast,assume that at Day 3, the tumor oxygenation is high, and the normalcell's susceptibility to toxic agents is low. In the latter, thisbehavior may be according to a predicted outcome or an unpredictedoutcome; if unpredicted, one might proceed to schedule take advantage ofthe favorable conditions for treatment and schedule an additionaltherapy session promptly (i.e., a favorable active treatment time). Ifpredicted, then the planned therapy can proceed as scheduled.

Determining Tumor Physiological Parameters

It is generally well accepted that tumor oxygenation and blood flow areimportant to the efficacy of most types of cancer therapy. Hypoxia (lowoxygen) and thus radiation resistance occurs in poorly perfused regionsof tumors (Gray et al., 1953). In addition, anticancer drugs of allkinds gain access to tumor cells through blood vessels, and poorlyperfused regions also hinder drug delivery (Jain et al., 1988). Forthese reasons, there has been great interest in developing methods formodifying and monitoring tumor blood flow and oxygenation, primarily tofind ways to increase radiation sensitivity. However, a knowledge oftumor oxygen levels can lead to alternative approaches, e.g.,hyperthermia effects which are enhanced in hypoxia (Stratford et al.,1994). More recent information on the influence of hypoxia in theregulation of genes and cytokines has continued to stimulate interest inthis area (Sutherland et al. 1994)). Further, it is likely that theseeffects are involved in influencing patterns of metastases (Young etal., 1997), angiogenesis (Schweiki et al., 1992) and drug resistance(Sakata, 1991).

Currently there is no commercially feasible clinically applicablenoninvasive method of assessing tumor hypoxia (McCoy, 1996). Magneticresonance imaging and positron emission (Robinson, 1998) have beendiscussed as possible means to monitor changes in tumor perfusion andblood oxygenation. However, these methods are cumbersome to monitor thedaily and dynamic changes, which occur during the perturbation of atumor. The ability to monitor tumor oxygenation and changes within thetumor during various challenges is important to improve cancer therapy.The information obtained can direct the type of and timing ofappropriate therapy, in order to increase the cytotoxic effect.

A substantial body of evidence has accumulated over the past 50 yearsindicating that electrode-evaluated human tumor pH is, on average, lowerthan the pH of normal tissue. However, strategies to explore thisdifference have been hampered for two reasons; first, overlap ofelectrode-measured tumor and normal tissue pH, especially when data ispooled. Second, more recent demonstration using 31P magnetic resonancespectroscopy (MRS) indicates that tissue pH can be divided into twocompartments: intracellular and extracellular—(a) pH determined byelectrodes primarily measure interstitial or extracellular pH and (b) pHdetermined by MRS primarily reflect intracellular pH (“pH_(i)”).Moreover, the pH_(i) of normal and tumor tissue is similar whereas theextracellular pH may vary significantly between normal tissue and tumorand tumor of the same origin but in different patients. For example, therange of pH in breast tumors has been demonstrated to be from 6.85-7.5and in the subcutaneous tissue of normal volunteers it was from about7.3-7.9.

The electrode-measured pH of tumors is on average 0.4 units lower thannormal subcutaneous or muscle tissue. Although overlap between normaland tumor tissue may exist, they may be explained by technical andpatient-related factors. However, the present invention recognizes thatmeasuring pH in both normal and tumor tissue at the same time and on acontinuous basis can eliminate this variation. The ability to accomplishthis can enable the physician to exploit the differences. Since theacidity increases with increasing distance from the supplying vessel andpH_(i) is similar in each tissue, the intra to extra cellular pHgradient may be expected to increase in those cells most distal fromblood vessels. The overall effect would be to enhance drug uptake andkilling of cells that are normally exposed to the lowest drugconcentration and especially relevant to radiation therapy in which lowoxygen concentration—and therefore radiation resistance—increases withincreased distance.

Accordingly, in one embodiment of the present invention, the sensor unit50 (whether self-powered and implantable or injectable with an inductivepowered version as will be discussed further below) can be inserted intothe tumor(s) and secured therein or thereto in order to gatherinformation, preferably for a number of weeks as discussed above. Asshown in FIG. 19B, the sensor elements 51 are configured such that theyare placed at different levels and in different locations in the tumor.It is also preferred, as is also shown in FIG. 19B, that at least onesensor element be configured to monitor the treatment toxic affect ornormal cells and/or the pH level of the normal cell tissue proximate thetumor.

It has been shown that a difference in oxygen levels exist between tumorfeeding arterioles (about 32 mm Hg) as opposed to the about a 50 mm Hglevel in healing or normal tissues. And as noted above, low oxygenlevels leads to treatment resistance in a tumor cell. If it isdetermined, with the aid of the device, that the majority of the tumoris hypoxic (i.e., less than 50 mm Hg, and preferably less than about 40mm Hg, and more preferably about 32 mm Hg or less), then it should notbe treated until the oxygenation of the tumor is improved. This canoccur in several ways. The tumor can be heated (hyperthermia) whichworks best in hypoxic conditions and which may eliminate enough cells tomake the remaining population less hypoxic, or the tumor can be exposedto specific drugs to improve the oxygen concentration. The importantpoint is that the tumor is not treated until more cells are oxygenatedand, therefore, more sensitive or vulnerable to the conventional activetreatments of radiation or chemotherapy. Similarly, the sensitivity and,therefore, cell kill of malignant cells can be affected by pH and cellproliferation. pH measurements of the tumor tissue would be important asthe pH can influence not only the delivery and uptake of drugs, but alsoaffect the oxygenation of the tumor. Therefore, if it is determined thatthe pH of particular tumor is 7.2 and the uptake of the drug of choiceis undesirably affected by a pH greater than 6.9, then the drug shouldbe withheld and the pH changed. Cell proliferation can be measured withthe aid of a beta radiation sensor able to monitor uptake of anyradioactive tagged substance or ligands and provide information on cellkinetics and proliferation. If the uptake of a particular ligand whichmeasures for cell proliferation is high (indicating active cellproliferation and therefore increased sensitivity), then the drug orradiation should be delivered.

It will be appreciated by those of skill in the art that at this time,specific dynamic changes and/or values of those changes occurring in pHor oxygenation of cell proliferation during and after treatment have notbeen definitively quantified (but which can now be established based onthe dynamic monitoring provided by the present invention). Further, thepH, cell proliferation rate and schedule, and oxygenation can varysignificantly from patient to patient, even within patient groups havingthe same type of tumor. Indeed, it is believed that this variability canaccount for the difference in response from patient to patient whentreated with the same drug. Why should only 10, 20, or even 30% ofpatients respond to a drug that, according to in vitro data, shouldproduce a tumor response of greater than 50%? Advantageously, thepresent invention will now allow data to be collected on specific valuesof for each monitored parameter or variable (preferably including pH,oxygen tension, and cell proliferation) during and following cytotoxictreatment. The collected data can be studied and a specific set ofvariables identified to affect a particular response. Armed with thisinformation, a patient can be more effectively treated. Thus, thepresent invention will now allow not only the establishment of specificvariable information for evaluation, but, can also be used to direct andmonitor the effects of treatment.

Thus, in a preferred embodiment, the present invention configures atumor monitoring system with sensor elements designed to monitor one ormore of tumor pH, oxygenation level, temperature, and cellproliferation. The cell proliferation can be measured presently by theuse of a radiation sensor (which can also be used to verify the dose ofradiation received at the tumor during radiation therapy). It isanticipated that other biochemical or biomolecules will be determined tobe sensitive indicators of the vulnerability of the tumor for treatmentand, thus, useful according to the present invention. The presentinvention can provide all these sensors in each tumor, gathering andtransmitting the information in real time, to a computer containing analgorithm to process the information to determine if and how the patientis to be treated.

Turning now to FIG. 4, an exemplary data analysis method is illustratedwhich evaluates and analyzes the data associated with the monitoredparameters. As shown, the desirable values of selected physiologicalparameters (shown as at least three parameters A, B, and C) areidentified or defined as they relate to the desired condition proximateto an active therapy (Block 200). The desirable values for each of theparameters may be input as a minima or maxima and may be cross-relatedto a particular treatment type. That is, one parameter, for discussionidentified as parameter “C” (such as pH), may require or desire acertain minimum or maximum value to achieve maximum effectivenessparticular to a certain treatment type (such as a particularchemotherapy or drug treatment). In contrast, another parameter, fordiscussion, identified as parameter “A” (such as oxygenation level) mayhave the same preferred value across all treatment regimes (typically aminimum value as a normal or an elevated oxygenation level isdesirable). As such, if there is a minimum or maximum value at whichtherapy should not proceed, it is identified as a test criteria for dataanalysis just prior to the delivery into the subject of the treatment.

Similarly, a range of physiological parameter values particular to theparameter can be used as a basis for test criteria; for example,defining the levels associated with “elevated,” “decreased” and “normal”can be input (Block 210). This criteria (as well as relative levels,population norms, or other indices of tumor behavior and treatmentefficacy) can then be used to define test conditions corresponding toevaluation of tumor treatments (Block 220). That is, the test conditionscan be any number of tests representing evaluation of the tumor and thetreatment. As shown, the test conditions also test for abnormal valuesof the monitored parameters (Block 231). This can identify themalfunction of a sensor, sensor element, or other component of themonitoring system as well as identify a potentially immediate need formedical evaluation. Other test conditions can include testing forelevated or decreased parameter values (Blocks 232, 233) respectively.Similarly, the presence of a clustering of “favorable conditions”represented by two of the parameters having increased or elevatedparameter values and another having a decreased parameter value (Block235) may represent a more favorable treatment period. For example, thepresence of an elevated oxygenation level together with a period ofincreased cell proliferation and a decreased pH level may trigger afavorable treatment window. Of course, the clustering of just the twoincreased parameters can also be a test condition. In addition, one testcondition can review the parameter values to determine variation from anexpected value based on a predictive model (statistically relevantvariation from a relative reaction or from a population norm) based on apoint in time during or after active treatment (Block 234). A testcondition which identifies whether the parameters meet the defineddesirable values may also be helpful (Block 236). It may also bebeneficial to have a test to determine if an expected data monitoring(local and/or remote) has been received or is missing (Block 237). Thiscould indicate data corruption, file corruption, or even be used toautomatically call the subject (such as with a programmed or recordedtelephonic message) to notify them that a data transmission is needed.

In any event, the physiological data is periodically monitored (Block240) and the data is compared to the test conditions/defined values(Block 250). An unfavorable active treatment time and a favorable activetreatment time can then be identified (Blocks 260, 261), respectively.Of course, other evaluations and therapy decisions can also be made. Thefavorable test time can be identified by the test conditions/parametervalues indicating a positive indicator (favorable condition or goodprogression). Of course, the data may also reflect a norm indicator(neutral condition), and a negative indicator (unfavorable condition orresistance to therapy). It is envisioned that a global network databaseor a regional database associated with each hospital or clinical siteidentifying the appropriate values can be pre-established tominimize-the data input needed for a particular subject.

It will be understood that each block of the block diagrams (or block inthe flowchart illustrations), and combinations of blocks in theflowchart illustrations or blocks in block diagram figures), can beimplemented by computer program instructions. These computer programinstructions may be loaded onto a computer or other programmable dataprocessing apparatus to produce a machine, such that the instructionswhich execute on the computer or other programmable data processingapparatus create means for implementing the functions specified in theflowchart block or blocks. These computer program instructions may alsobe stored in a computer-readable memory that can direct a computer orother programmable data processing apparatus to function in a particularmanner, such that the instructions stored in the computer-readablememory produce an article of manufacture including instruction meanswhich implement the function specified in the flowchart block or blocks.The computer program instructions may also be loaded onto a computer orother programmable data processing apparatus to cause a series ofoperational steps to be performed on the computer or other programmableapparatus to produce computer implemented process such that theinstructions which execute on the computer or other programmableapparatus provide steps for implementing the functions specified in theflowchart block or blocks and/or block diagrams.

Accordingly, blocks of the block diagrams or in a flowchart illustrationsupport combinations of means for performing the specified fuctions andprogram instruction means for performing the specified functions. Itwill also be understood that each block of the block diagram orflowchart illustrations, and combinations of blocks in the blockdiagrams or flowchart illustrations, can be implemented by specialpurpose hardware-based computer systems which perform the specifiedfunctions or steps, or combinations of special purpose hardware andcomputer instructions.

Although the present invention will likely provide additional basis forestablishing more definitive numbers or values for monitored tumorphysiological parameters, the following parameters and levels andindicators are provided as suitable for establishing test criteriaassociated with treatment or tumor condition.

Conventional treatments use combination therapies such as temperatureand radiation (tumor heated twice a week while irradiating every day).

Temperature

One approach to the treatment of large unresectable tumors is the use ofradiation and thermal treatment. Typically, in such instances, the tumoris irradiated daily and heated twice per week following the dailyradiation treatment. The temperature range preferred to achieve anincreased, and hopefully maximum, cell kill is between about 42-43.5° C.This temperature is then preferably maintained for about 20 minutes. Thetemperature is monitored closely to minimize the effects on thesurrounding normal tissues and to assure that the same temperature issubstantially homogeneously obtained throughout the tumor. Thistreatment technique is utilized and found to be effective for primarytumors from a number of tumor sites, including, but not limited to, thelungs, the prostate, the breasts, melanoma, the pancreas, and thepelvis. Thus, the present invention can provide an easy and effectivethermal monitoring means by which temperature can be monitored, thethermal monitoring can prove especially suitable for externallyinaccessible tumors or for tumors located deep within the body, whichare not easily monitored by conventional means.

Level of Oxygenation

The oxygenation level need to overcome radiation and or chemotherapyresistance has not been definitively established on dynamic systems asnoted above. That is because, the precise changes which occur duringtreatment have not been quantified and therefore it is difficult topredict what definitive value may ultimately be established as necessaryto overcome radioresistance now that dynamic monitoring protocols areavailable. This information will be obtained upon clinical applicationsof the proposed invention along with specific correlation withtreatments and responses. Ultimately, lower oxygen tension may be foundto be effective for treatments and that a normal or elevated oxygenationis not required for successful treatment. Nonetheless, the currentpreferred treatment approach is to achieve at least as normal a level aspossible (and not to deliver during decreased oxygenation periods).Accordingly, for reference, the term “elevated” can be described aslevels above 52 mm Hg. The term “normal” can be described .as levelsfrom about 50-52 mm Hg. While the term “decreased” can be described aslevels at or below 49 mm Hg, and more preferably, below about 40 mm Hg.It should be noted that oxygen is important for most, if not all tumortypes, and is not specific to one type of tumor (although a particularlevel may be more suitable for treatment of one type). Further, in situsensors according to the present invention can be positioned atdifferent positions within the tumor to monitor the distribution ofoxygen. If a significant difference (or delta) is detected, an attemptcan be made to increase the oxygen levels to a sufficient level acrossthe tumor.

Accordingly, the radiation or chemotherapy treatment can be withheld andgiven only when the oxygenation level approaches a minimum of about 50mmHg or is within a range determined to be appropriate for that patient(based on a relative response and/ or absolute response data).

Cell Proliferation

As noted above, cell proliferation is an important property of malignanttumors which can effect outcome. A knowledge of the time during whichthe tumor cells are proliferating is important in order to achieve agreater cell kill, and in turn, a greater response to therapy and animproved outcome. The degree of cell proliferation is related to thenumber of cells, which are cycling. Thus, if a ligand associated withcell proliferation is tagged, it will be incorporated into cycling cellsand reveal itself as increased radioactivity within the tumor. Undernormal or quiescent conditions, only about 2-5% of cells are typicallycycling. This quantity will increase generally by an order of magnitudeto 20-25% in a moderate or highly proliferative state. The difference inuptake of the radioactive material will be noticeable and can becorrelated to periods of increased cell proliferation. The time duringwhich this increased proliferation is not readily known and has not beenreadily identifiable. The time during which cell proliferation occursmay vary with the specific tumor type, as well as the rate ofproliferation itself (the time it takes to double the population).

Tumor pH

The pH of tumors has been found to be lower (more acidic) than the pHassociated with normal tissue. The precise pH or range of pH needed formaximum effect is not known, nor have the fluctuations encounteredduring treatment been quantified as noted above. The impact ofinformation regarding pH can be more complicated than that oxygen sincepH may effect oxygen level, drug uptake, and cell proliferation. Inaddition, surrounding normal tissue can also effect the tumor pH. Atpresent, it appears that a more acidic environment (pH of between about6.8-7.0) may be preferably for treating malignancies. This is based onin vitro data which indicates that at least one drug, adriamycin, ismore effective at low pH. As also noted above, the difference in pHbetween normal and malignant cells can be narrow (about 0.4 units) andtherefore may indicate that there is a narrow treatment range at whichdrugs and radiation are more effective. As noted above, the presentinvention can now determine, in real time, the changes that occur duringand after cytotoxic therapy.

Radiation

Radiation monitoring can be used to identify cell proliferation above(typically beta radiation). Radiation sensors can also be used to verifyirradiation doses delivered during photon irradiation treatment(typically in the range of between about 3000-6000 cG). Thus, use of aradiation monitor during real time delivery can help control a moreprecise delivery dose of gamma radiation to the tumor site (distributionof dose within the tumor following photon irradiation or verification ofcalculated dose, especially with high dose conformal therapy). βradiation monitors can also monitor radioactively labeled compounds tomonitor drug uptake and utilization, blood flow the tumor, sensitivityto specific drugs, drug distribution in various organs (as well as cellproliferation discussed above).

In summary, a number of tumor (and proximate normal cell) parameters canbe monitored, each of which can provide information material to thetreatment and condition of a tumor in a subject. Individual parametercombinations thereof, and biomolecular tumor parameters yet to beidentified may also be monitored according to the present invention.

Biotelemetry and Implantable Sensors

It will be appreciated by one of skill in the art that when a foreignobject is implanted into the body, a series of host responses occur: 1)deposition of blood plasma proteins, 2) fibrin formation, 3) assault byimmune cells and proteins, 4) attack by inflammatory cells, and 5)formation of a cellular capsule around the object (Reichert et al.,1992). Therefore, it is important that the materials used in animplanted device address this host response. Much is known about theimplantation of sensor systems. Kapton® polymers have been shown to berelatively benign when used as a sensor substrate (Lindner et al.,1993). Pacemaker companies frequently use titanium cases with medicalgrade epoxies and silicone rubber to encapsulate the external leadconnections (Webster, 1995). Implantable glucose sensors have beenconstructed using polyethylene cases covered in Dacron velour, with thesensor surfaces being coated with a variety of bioprotective membranes(Gilligan et al., 1994). (These units were wet sterilized in 0.05%thimerosal for 24 hours before being implanted and tested in vivo for upto three months.) A more common method used for sterilizing implantdevices is gas sterilization at temperatures of 115° C. to 120° C. for20 minutes.

Early researchers used discrete components to implement simpleoscillator circuits for implantable sensors (Mackay, 1995). In recentyears, the focus has been on miniaturization, using hybrid andintegrated circuits for the electronic portions of the systems. Becausethe demand for “high-tech” biotelemetry systems in the past has beensmall, few suppliers have invested resources into developingstate-of-the-art systems and devices. Most of this development has beenperformed at academic institutions around the world, with an emphasis oncreating smaller, more-efficient telemetry and telemetry-like deviceswith increased functionality.

Integrated circuit (IC) technology has been used significantly forbiotelemetry device electronics throughout the past two decades. In themid 1970s, IC usage was made feasible through the use of hybridtechnology. This technology enabled engineers to construct telemetrydevices by interconnecting commercially available ICs, simple customICs, and other discrete components, on ceramic substrates through theused of thick- or thin- film technologies (Fryer et al., 1973; Deutsch,1979; Gschwend et al., 1979; Donald et al., 1981). Perhaps the bestexample of this technology is a unit perfected at NASA Ames (Hines etal., 1995). NASA uses a carrier of 455 kHz and digital PCM. Theimplanted unit is fabricated using hybrid technology and monitors pH,heart rate, temperature, and battery voltage. Its current consumption isless than 120 microamps drawn from a 0.75 A-hr lithium battery. Thebattery lifetime is 6-9 months. The unit is packaged in acustom-manufactured, diskshaped ceramic package, approximately 3.0 cm indiameter occupying a volume of 20 cc. The telemetry link has anacquisition range 12 to 24 inches.

As the microfabrication processes improved, telemetry units could befabricated on individual silicon substrates only millimeters in lengthand width. Recently, biotelemetry systems have been appearing withcustom integrated circuits as a major component (Oshima et al., 1987;Williams et al., 1994; Wouters et al., 1994; Akin et al., 1995). In atypical example (Puers et al., 1993), an intelligent 4-channel unit wasdesigned and fabricated for animal husbandry studies. The electronicsused for this device were created on a 4.7×7.1 mm² silicon substrate andincluded both analog and digital signal conditioning electronics toprocess the incoming signals, transmit them accordingly, and directpower to the appropriate sub-circuits when needed. As with most IC basedtransmitters, a few external devices were required for operation,including capacitors and crystals for driving the IC oscillators,accelerometer and temperature sensors, and resistors and switches to setgains and identification codes. It is important to note that suchadditional components can be undesirable, since they can add to thephysical size of the electronics and increase the overhead involved infabrication. They do, however, give the user/designer more flexibilityin modifying circuit operation.

A novel implantable telemetry system was recently under development atNorth Carolina State University (Fernald et al., 1991 and 1992). Thesystem was intended for rapid-prototyping applications, and was designedsuch that a nonengineering researcher could construct a customizedimplant device with minimal effort. The system consisted of two coreintelligent integrated circuits, a microprocessor/telemetry chip and adata acquisition chip that could be stacked upon one another and fullyinterconnected with less than ten bus wires. Although the dataacquisition chip provided eight input channels, additional channelscould be attained by stacking additional such chips and attaching themto the bus lines in a daisy-chain manner. The microprocessor was fullyprogrammable (both before and after implantation) and possessed aninstruction set suitable for processing biological signals. The systemwas intended for a variety of transducers with varying bandwidths. As aconsequence of the serial bus architecture, the system throughput waslimited to an aggregate bandwidth of 20 kHz, suitable for mostapplications.

Researchers have long sought methods to eliminate the batteries inimplanted devices (Hansen et al., 1982). Inductive power coupling hasreceived attention in recent years. One research group (Benedetti, 1995)developed an inductively powered implant with four channels formeasuring pressure and EMG. The sampling rate was 200 Hz/channel; itssize, 15×19×86 mm³; and its weight, 55 g (40 g is the housing). Theimplant was mounted in a gold-plated brass housing. Surface mountedcomponents were attached to stackable printed circuit boards. Theinternal power sources were +3 V and −3 V, derived from a power carrierfrequency of 27.1 MHz. Current consumption was 6 mA. Thetransmission/coupling range was 30-70 mm. The telemetry links weresampled FM with a frequency range of 36 kHz-120 kHz.

A second example system incorporating inductive powering was designedfor orthopedic measurements (Graichen et al., 1991 and 1995). This unitimplemented eight telemetry channels (6 for strain sensing, one fortemperature, and one for power supply voltage). The electronics modulewas a thick-film hybrid substrate with custom IC and discretecomponents. The substrate was encapsulated in a titanium cylindermeasuring 8 mm in diameter and 27 mm high. The telemetry links operatesusing pulse-interval modulation with a carrier frequency of 150 MHz. Theoperating range is 20 cm. The implant is inductively powered through a 4kHz coupling channel.

Inductive powering is also finding applications in cardiovascular andneural studies. A novel 3D power steering scheme has been proposed forhigh-data rate cardiac mapping studies (Mueller et al., 1995).Researchers have also implemented inductive powering in sometelemetry-controlled neural stimulators. Their size has been greatlyreduced, allowing them to be injected into tissue through a hypodermicneedle. Two such devices have been reported by researchers at theUniversity of Michigan (Akin et al., 1990) and the Illinois Institute ofTechnology (Loeb et al., 1991). Both systems rely on micro coils andmagnetic induction to power the devices, thus eliminating the size andweight associated with batteries. The inductive links were alsomodulated to convey command information to the implants. Furtherreduction in size was achieved through CMOS integrated circuittechnology. Both research groups proposed incorporating reversecommunication capabilities, so that the implanted devices can alsoperform telemetry monitoring functions (Nardin et al., 1995).

Commercial manufacturers have been successful in building and marketinga variety of models. These systems only have a few channels and aretailored for animal research. For example, Data Sciences International(St. Paul, Minn.) offers a number of models. Their systems usepulse-interval modulation, a low power consuming technique. However,their systems typically use a single carrier frequency per channel,limiting the number of channels that might be implemented. The low inputimpedance of their electronics also limits the possibility of includingpH and other ion-selective sensors. Another limiting factor in the DataSciences system is its unique, proprietary signal encoding,transmission, and receiver units. Therefore, the possibility ofexpanding beyond four channels (their upper limit) is quite unlikely.Coupled with the fact that these units are larger than needed and thatthe upper limit is 35° C. for their temperature sensors, Data Sciencesunits are not appropriate for this application.

Telemetry units from Mini Mitter (Sun River, Oreg.) are very small insize (XM-FH series—9.0 mm (dia.)×15 mm; VM-FH series—12 mm (dia.)×19mm). They use the pulse interval modulation transmission mode to achievevery low power operation. However, they monitor only a single channel.Therefore, stacking several single channel transmitters to build amulti-channel device could make the combined size unacceptable. Smallbutton-type batteries are used and are easy to replace. These units areattractive for single channel applications.

Biotelemetrics (Boca Raton, Fla.) builds transmitters whose carrierfrequency is adjustable, which makes it possible to stack a series ofsingle channel transmitters to make a multi-channel unit. The size of atypical unit is approximately 2.5 mm×7.5 mm×10 mm. The transmitters canbe turned on and off periodically to reduce the power consumption. Theelectronics exhibits a high input impedance which enables the unit to beconnected to any kind of sensor (e.g., thermistors, pH sensors, andother ion-selective sensors).

Konigsberg Instruments (Pasadena, Calif.) offers four- and eight-channelimplants for measuring temperature and biopotential signals (such asEEG, ECG, and EMG) with a bandwidth up to 1 kHz. The units range in sizefrom the smallest 1.0 cm×1.5 cm×3.3 cm to the largest 5.1 cm×2.3 cm×1.5cm. The units are battery powered and the battery life ranges from fiveto 20 months. An RF switch is included to turn the battery on and off.The transmit range is typically 3-5 m. Multichannel amplifier units arealso available to receive the transmissions from the implants and relaythem to a remote base station. Several other small companies makebiotelemetry devices (Bio-Sentry, CME Telemetrix, Coulbourn, MIEMedical, Micro Probe, Telefactor, and Transkinetics), but they are notimplantable or are single-channel units (Biotelemetry Page, 1997).

Button battery cells have been available for nearly three decades, andwere extensively used in hearing-aid devices. The most commonly usedcells of this type are available in two chemistries—zinc-mercury oxideand zinc-silver oxide. The primary functional differences between thetwo are as follows: (1) zinc-mercury oxide exhibits a flatter dischargevoltage characteristic over time, (2) zinc-mercury oxide responds betterto momentary high-power demands (low internal resistance), (3)zinc-silver oxide has a higher output voltage, specifically 1.5 to 1.6V, versus 1.35 V from zinc-mercury oxide, and (4) the volumetric energydensity of zinc-silver (monovalent) is greater ranging 400-550 Wh/cm³.The service capacity of these cells is typically near 100 mA-hours.

Another alternative to these cell types are the recent lithium-anodebased cells. These cells are desirable because their output voltages(near the 3 volts needed for ICs) are typically twice that of zinc-anodecells. Another notable difference is that lithium cells are typicallyavailable in flat packages and are appropriately termed “coin-cells.”From a volumetric standpoint, the energy densities of most lithiumbasedcells compare favorably to zinc-based cells. For example, lithium-iodinecells exhibit a 2.8 V output with a high energy density of approximately1,000 Wh/cm³. Pacemakers have used lithium cells since the 1970s.

Preferred Tumor Monitoring Devices

Some preferred sensor embodiments of the present invention areillustrated at FIGS. 5, 6A, 8, 9, and 22. Generally described, the insitu sensor units 50 of the present invention are configured to be oneof implantable or injectable into the subject. FIGS. 5, 6, 21, and 22illustrate preferred implantable embodiments, while FIG. 8 illustratesan injectable embodiment. FIG. 9 illustrates a hybrid sensor unit 50″having both an implantable satellite sensor body 50S and associatedinjectable dependent sensor bodies 50D. Each of the sensor units of thepresent invention are powered either by a battery (FIG. 5), or, and morepreferably, is inductively powered (FIGS. 6A, 8, and 9). Each of the(implantable or injectable) sensor unit bodies is hermetically sealedwith biocompatible materials and sterilized by methods well known tothose of skill in the art.

As shown in FIG. 5, the sensor unit 50′ is configured with at least onesensor element 51. The sensor element 51 shown in FIG. 5 is athermistor. More preferably, as shown in FIG. 6a, the sensor unit 50comprises a plurality of sensor elements 51 a-51 e, which are preferablyconfigured to monitor one or more of temperature, radiation, oxygen, andpH. Suitable discrete pH, radiation, and temperature elements 51 a-51 eare known to those of skill in the art. The preferred temperature sensortype is a thermistor. The preferred radiation sensors are well knownsuch as MOSFET (metal oxide semiconductor field effect transistor) baseddesigns. Preferred self-calibrating oxygen and combination oxygen/pHsensor embodiments will be discussed further below.

The temperature sensor element for the present invention is configuredto operate in the temperature range of about 35° C. to 45° C. with anaccuracy of about 0.1° C. Size is of major importance since the entireimplantable device should be minimally invasive. Preferably, the entireimplantable sensor unit is sized to be less than about 1.0 cm³. Further,the sensor units 50, 50′, 50″ of the tumor monitoring system 10 areconfigured to operate even when exposed to a radiation field. That is,the sensor unit 50, 50′, 50″ do not necessarily have to function whilethe radiation is being administered to the tumor, but they preferablyfunction immediately afterward. The sensor unit 50, 50′, 50″ is thusconfigured to respond quickly (within a few seconds) after radiationadministration. In a preferred embodiment, as shown in FIG. 8, thesensor unit 50″ is sized and configured such that it can be placed onthe tip of an insertion probe and injected via a large bore canula suchas via image guide placement into position. Referring now to FIGS. 6Aand 6B, a preferred embodiment of a sensor unit 50 is shown. The sensorunit 50 is configured with a primary body portion 50B and a plurality ofarm portions 50A extending outwardly therefrom. As shown in FIG. 6B, thearms 50A have a thin planar profile. Preferably, the arms 50A are formedof a flexible biocompatible substrate material such as a polyimide (likeKapton®, a polyimide material). At least one sensor element 51 ispositioned on each arm 50A, preferably at a distal portion (away fromthe primary body 50B). A separate channel 151 electrically connects thesensor element 51 to the electronic operating circuitry 125 positionedon the primary body 50B. Of course, a plurality of sensor elements 51can be positioned on each arm, each with a separate electricalcommunication channel 151. Preferably, each channel is defined by a pairof leads (the sensor O₂ may have greater than two (2) leads) formed bymetal vapor deposition onto the top surface of the flexible substrate.

As is also illustrated by FIGS. 6A and 6B, the transmitter coil 58 issubstantially circumferentially layered to surround the electronics 125.The electronic circuitry 125 includes at least one, and preferably aplurality, of fixed resistors 125R for signal data reference as will bediscussed further below.

As shown in FIG. 6B, a biocompatible coating 160 is applied (topreferably encasulate, and more preferably, hermetically seal) to theexterior of the sensor unit 50. Surface mounted electrical componentscan also be located on the bottom surface of primary body 50B, withinterconnection being made by plated through vias (a common method usedin flexible printed circuit board technology). Advantageously, thismulti-arm configuration can provide increased regional data to allow formore informal analysis of the tumor. As discussed above, the multiplesensor elements 51 can contact different locations within (penetrate atdifferent depths) and/or wrap to contact different exterior perimeterlocations along the tumor. Alternatively, one or more arms can beattached to normal tissue to provide information regarding the status ofsame. In any event, the sensor arms 50A are preferably configured withattachment means 150 to secure their position in the subject. Forexample, sensor element 51A illustrates an aperture 150 formed in adistal position of the substrate to allow a suture to attach it inposition. Alternatively, sensor element 51 b illustrates a barbed outersurface 150′.

FIGS. 7, 8A, and 8B illustrate a sensor unit 50″ which is cylindricallyshaped and sized for injection, e.g., an injectable sensor unit 50I. Inthis embodiment, a PCB or IC chip 125 p is oriented to extend a smalldistance along a length of the sensor body. The coil 58 alsocylindrically extends to surround a portion of the PCB or IC 125. In theembodiment shown, the PCB is a substrate (preferably a flexiblesubstrate) which extends a distance outside the coil 58 (for an overalllength which is less than about 0.5 inches). Of course, with the use ofan IC configuration, this size can be further reduced. In addition, theIC or PCB can be configured and sized to extend substantially the samedistance as the coil 58. The sensor body can be configured to hold asingle channel (i.e., one sensor element for a PCB version having awidth of about 3 mm) or multi-channel (multiple elements, with eachchannel layed side by side, and typically wider than the single channelversion). The tip 125T of the sensor unit 50I can be configured with arounded or pointed edge to help facilitate entry into the tumor tissue.Again, the entire sensor body is encapsulated with a biocompatiblematerial and sterilized for medical applications.

Preferably, both the injectable and implantable versions 50I, 50,respectively, of the sensor units of the present invention, such asthose shown in FIGS. 6 and 7, are inductively powered. That is, themonitoring system is configured to act as a transformer (with one coilon the surface of the patient's body and the second within the monitor)to couple and power the internally disposed sensors, as is well known tothose of skill in the art and discussed briefly above. As such, the insitu sensor units 50, 50′, 50″, 50″′ are self-contained, and have asufficiently long service life in the body to provide clinically usefulchronic information for episodic or chronic treatment decisions, and canbe miniaturized without requiring catheters or externally connected wireleads into the sensors and out of the body.

Alternatively to the separate copper wire wrapped coil conventionallyused to form the coil 58, the coil 58 can be integrated into the circuitboard itself via a ferrite substrate (a flux concentrator). Further, thecircuit board 125 p and its associated electrical components can beconfigured as a miniaturized chip which allows the coil 58 to besimilarly miniaturized. Note, however, that the signal is typicallyproportional to the area of the coil and, as the area of the devicedecreases, the signal strength associated with the coil 58 on or aroundthe device can decrease.

It will be appreciated that to further miniaturize the device, thetemperature sensor resonant element can be configured as a positivetemperature coefficient (PTC) (typically ceramic). Although mostconventional devices employ NTC (negative temperature coefficient)versions, for the instant application, the PTC may be advantageous.

FIG. 9 illustrates a hybrid sensor unit 50′″ version of the inductivelypowered implantable and injectable sensor units 50, 50I described abovewhich allows for miniaturized sensor element bodies and useful signalstrength at transmission. As shown this sensor unit 50′″ embodimentincludes a satellite sensor unit 50S with the IC or externallycommunicating electronics 125 thereon and a plurality of dependentsensor units 50D. The dependent sensor units 50D are inductively coupledto the satellite sensor unit 50S which is, in turn, inductively poweredand coupled to the external system. Further, the dependent sensor units50D are telemetrically connected 60I to the satellite sensor units 50I,which is telemetrically connected 60 to the external receiver 75.Because the dependent sensor units 50D are locally positioned relativeto the satellite sensor unit 50S, the signal strength demands arereduced, thereby allowing the injectable sized dependent sensor units50D to be further reduced in size. Preferably, each dependent sensorunits 50D, can be electronically encoded or identified or positionallyrelated to a particular channel or port within the satellite sensor unit50S to maintain relative (if not absolute) positional information forconsistent data analysis of the transmitted sensor data for themonitoring system 10.

FIG. 19A illustrates another embodiment of the present invention, atleast one wherein the tumor monitoring system 10′″ employs a pluralityof sensor units 50. That is, at least one sensor unit 50 is positionedat a different (separate) tumor site as shown. This multi-sensor unittumor system 10′″ can result in more regional specific information toadjust treatment as necessary to effective in each tumor site ofconcern. Preferably, the multi-sensor monitoring system 10′″ willconfigure each separate sensor unit 50, 50″, 50″′ to be electronicallyidentifiable to maintain data integrity and correlation to the tumorsite/particular location. This can be provided by configuring thereceiver 75 and the separate sensor units 50 (50I and 50S/50D) with portcommunication protocols to identify and/or maintain the relative orderof transmittal to the location or position of the particular sensor unit50 within the body (i.e., channel one for “sensor 1,” channel 2 for“sensor 2,” each alphanumeric identifier being manually or programmablyset at insertion or position onto the tumor in relation to its left toright or up to down position to a relational axis). As the receiver 75should be positioned proximate to the sensor unit coil 58 (typicallyabout 30 cm) for proper data transmission, it is preferred that thereceiver 75 be configured to move to overlay the appropriate sensor unitduring transmission (indicated by the arrow and dotted line movement ofthe receiver in FIG. 19A) and it is also preferred that the receiver 75be programmed to recognize the order of sensor unit transmission toassure data integrity. Of course, two receivers can be used, one foreach sensor unit location. This may be especially appropriate fornon-clinical use, such as at a patient's home wherein a patientinteractive system may be needed. Thus, a dual receiver configuration,whereby a user can keep in position a portable receiver over eachmonitored tumor site, can be advantageous.

Of course, an external mark or indices of alignment to allow properalignment may also be helpful (both in a single tumor/region sensor unitembodiment and a multi-sensor unit/spaced position embodiment). This canbe a semi-permanent physical mark 175 made on the skin and/or otherinfrared or photogrammetric position readable or indication means whichcan cooperate with the receiver 75 (receiver loop) such that thereceiver 75 can send out a position verification beam to facilitateproper alignment before/during transmission at the selected location.

For remote transmissions, the tumor monitoring systems of the instantinvention are preferably configured to transmit information at a low orvery low bandwidth. That is, the carrier bandwidth is preferably in theMHz range while the modulation frequency is more preferably at or belowabout 1 kHz. This low bandwidth operation allows transmission of signaldata received from the sensors across slow communication links such asmodem and voice telephone connections. Preferably, the measured signalinformation is encoded into one of several time-based modulationschemes. The time-based encoding permits accurate data transmissionacross communication links that may convey amplitude informationinaccurately and frequency information accurately, such as the voicetelephone network. In addition, for home site non-clinical use tumormonitoring systems 10′, the monitoring equipment is preferably small andrelatively inexpensive or cost-effective to be set-up and operated atremote locations.

Of course, the low bandwidth operation is not required as the data fromthe sensor units 50, 50I, 50S can be converted into essentially anynumber of suitable encoding or transmission schemes that are suitablefor remote operations, as discussed above, such as substantiallycontinuous or semi-continuous monitoring with a PC at the remotelocation and storing the data associated with same with time/date stampsso that a complete data set or data segment/record covering a period ofhours, days, weeks, or longer can be gathered and transmitted to thecentral processing site over one or more discrete relatively short datatransmitting sessions.

Of all of the major types of temperature sensors, typically thethermistor is by far the most sensitive. It has a fast response time anda high output for interfacing, and small devices are commerciallyavailable. The non-linear response is not critical over the smalltemperature range in which the sensor will function (typically less thanabout 10°). Although the interfacing circuits require a current source,the silicon overhead is only a few additional transistors. The device isconsidered fragile for industrial purposes, but should be amply ruggedfor this application. Sensor self-heating is reduced since the deviceoperates in a limited temperature range and the current can be small andneed not be applied continuously. If a battery source is used, thesensor element is preferably insulated or positioned spatially away toreduce its exposure to heat attributed to the battery.

To validate a tumor sensor design, a single-channel, discrete-component,commercial telemetry unit was purchased (Mini Mitter, Inc., Model VM-FH)with externally mounted thermistor. An experiment was conducted atTriangle Radiation Oncology Services (TROS) by placing the thermistorand transmitter into an agar-gel phantom target, and heating the targetin a hyperthermia treatment device (Thermotron RF-8) over thetherapeutic range of 37° C. to 45° C. FIG. 2A illustrates the principleof operation of a hyperperthermia treatment with a Thermotron® device.An eight MHz RF signal is applied between the plates of the machinewhich causes ions between them to oscillate. These oscillations generateheat by friction, producing uniform self-heating of body tissue. Theagar-gel phantom is approximately the size of a human torso and mimicsthe heating characteristics of body tissue. During treatment sessionswith a patient, the skin surface temperature is always monitored. Inaddition, catheters are normally inserted through the skin surface intothe tumor undergoing treatment and its vicinity. During treatment,thermocouple probes are inserted through these catheters to record tumortemperatures as the RF energy is applied. These catheters are left inplace in the patient between treatment sessions and are frequently asource of discomfort and infection.

This experiment was designed for two purposes. First, the performance ofthe insulated thermistor was compared to that of a Thermotron®thermocouple, and secondly, to observe the heating effects of theThermotron® device's RF energy on a bare, button-sized battery placed inthe agar-gel. The experimental setup is illustrated in FIG. 11. Twocatheters 99 were inserted into the agar-gel phantom 101: one positionednear the thermistor 99R and the second near the battery 99B. Thermotron®device thermocouple probes were inserted into the catheters and RFenergy was applied to the agar-phantom to gradually sweep itstemperature over the therapeutic range. The experiment was designed tobe conducted over a 75-minute time period to ensure that the agar gelwas heated uniformly.

The results of the experiment are presented in Table 1. The first twocolumns of Table 1 show the time progression of the experiment and thetemperature reading from the Thermotron® device's instrument panel takenfrom thermocouple-1 (see FIG. 11). This measurement was assumed to becorrect and was used as the reference or “gold” standard. The thirdcolumn shows the relative change in the temperature of thermocouple-1from its initial value in the first row. The fourth row shows therelative change in the thermistor's readings at the same measurementtimes. Note the close correlation with the Thermotron® device'sthermocouple readings.

The results of the button battery heating experiment are reported in thefifth column of Table 1. These data were recorded from a thermocouple-2located near a button-sized battery placed in the agar-gel phantom. Notethat the temperature near the battery increased to a larger extent asthe RF energy of the Thermotron® device heated the agar-gel over thetherapeutic range. While the temperature of thermocouple-1 near thethermistor increased by 8.8° C., the temperature of thermocouple-2 nearthe battery increased by 11.1° C. This indicates that any implant thatis powered by a battery should be properly thermally insulated tominimize its temperature sensors that are monitoring the environment oftumor cell populations.

TABLE 1 Agar-Gel Phantom Experimental Results. Thermo- Thermo- TimeThermocouple-1 couple-1 Thermistor couple-2 (minutes) Temperature (° C.)(T) (T) (T) 0 35.7 0 0 0 7 36.9 1.2 1.2 1.6 24 38.5 2.8 2.8 3.7 37 41.05.3 5.3 6.6 57 43.5 7.8 7.9 9.7 72 44.5 8.8 8.7 11.1

The next task was devoted to designing and building a 4-channel,discrete-component prototype circuit using breadboarding techniques.This circuit utilized four thermistors for temperature monitoring. Ablock diagram of the circuit is illustrated in FIG. 12. Temperatureincreases were sensed by the four thermistors 51 a-51 d in response to acorresponding reduction in resistance. A constant current source drivingthe thermistors 51 a-51 d was used to measure the resistance. Theamplifier 53 voltage output was proportional to the resistance change. Avoltage to current converter 54 attached to the amplifier 53 was used tocharge a timing capacitor 56. The time period for the voltage on thetiming capacitor to reach a threshold was proportional to the change inresistance in the thermistor 51 e, and hence proportional to thetemperature change at the thermistor's surface. FIGS. 13 and 14A-14Cshow suitable operational design for sensor circuits. When the capacitorvoltage reaches a preset threshold, the transmitter 157 sends a signalburst at 1.0 MHz to the coil 58. At the same time, the thresholddetection circuit 158 discharges the capacitor 56. At the end of thesignal burst, the capacitor 56 is allowed to again begin charging towardthe threshold value. If the amplifier 53 voltage is high, a largecurrent is dumped into the capacitor 56 leading to a short charging timeinterval. If the voltage on the amplifier output is zero, then nocurrent is dumped into the timing capacitor 56. In this case, a smallcurrent source was included to ensure that the device is operatingproperly. This small current source forced the transmitter 157 to sendout signal bursts at a large time interval for testing purposes. Longertime intervals indicate lower temperature measurements, while shorterones indicate higher temperatures.

The clock, counter, and control logic 155, 156 serve to multiplex thefour thermistors 51 a-d over the biotelemetry channel in a round-robinfashion. A modified AM radio receiver attached to a laptop PC runningLabVIEW® software (National Instruments, Inc., Austin, Tex.) was used todetect the transmitter bursts. Water bath experiments were used tovalidate the operation of the implant design. The range of the telemetrylink was about 30 cm.

Following the design and construction of the discrete-componentbreadboard, a surface-mount (SMT) unit was designed and constructed toreduce the size. The circuit of FIG. 12 was refined and a double-sided,2.5×3.5 inch, printed-circuit (PCB) was fabricated. Low profile SMTcomponents were used. The power consumed was 4.5 W from a 3.0 V battery.The transmitting coil 58 (13.5 mm in diameter) was formed with 25 turnsof #38 AWG copper wire, producing a range of 30 cm. Four thermistors 51a-d were attached to the device and the water bath experiments wererepeated. Results were similar to the earlier experiments verifying thefunctionality of the system.

Following the successful SMT experiments, a first-generation integratedcircuit (IC) test chip was designed. Its purpose was to demonstrate thatthe operating concepts adopted for the SMT unit can be adapted forintegrated -circuit technology. FIGS. 15 and 16 depict the functionalblocks of the IC design and its chip layout. The circuit design wasfirst refined and simulated using SPICE. Then an IC layout was performedusing standard cell technology. The circuit was specifically designed tominimize its susceptibility to latch-up. The test chip was implementedusing the MOSIS fabrication service (2.0 micron, CMOS, n-well,low-noise, Orbit analog process, tiny-chip frame). Several internal testpoints were inserted to allow complete testing of the IC subcircuits.Four ICs delivered in dual-in-line (DIP) packages were mounted in an ICprototype unit constructed using a small PCB (1.5×4.0 cm). All four ICswere subjected to benchtop functional testing and performed as expected.

After passing the functional tests, the test chips were exposed to aseries of radiation and thermal tests. First the units were thermallytested using a temperature-controlled water bath as shown in FIGS. 17Aand 17B. The IC prototype unit used seven channels for sensor data. Fourof the channels were connected to thermistors and the remaining threewere connected to fixed resistors. FIG. 17A illustrates that thethermistors caused the channel pulse width to vary by approximately 0.03ms per 0.1° C. while, as shown in FIG. 17B, the fixed resistor channelsvaried by about 0.003 ms per 0.1° C. These results are well within theaccuracy specifications for tumor sensors according to the presentinvention.

Next the units were exposed to radiation using the cancer treatmentfacilities of Triangle Radiation Oncology Services (TROS) located at RexHospital in Raleigh, N.C. A series of 400 cGy radiation doses weredelivered with a Varian Clinac 4/80 at a source to surface distance of80 cm and a dose rate of 1.2 Gy/min. The IC prototypes were not poweredduring exposure, simulating one clinical environment in which theimplants can be employed. The results of the radiation exposure testsare displayed in FIGS. 18A and 18B. Note that the thermistor and fixedresistor channel pulse widths change by approximately 0.001 5 ms per Gy,which translates to approximately 0.005° C. per Gy. Given that a patientis not typically exposed to more than 8000 cGy, the impact of radiationis less than 0.4° C., which can be corrected by signal processing asdescribed below.

The thermistor and fixed resistor data in FIGS. 18A and 18B suggest thatthe increase in pulse width during exposure to radiation is due tochanges in the active transistor parameters of the IC. These parameterchanges are expected based on the experience of many researchers in theeffects of radiation upon microelectronic circuits (NPS, 1997).Therefore, the IC device can be considered as a sensor for the radiationexposure.

Accordingly, a fixed resistor channel can be used to measure totalexposure. From calibration data for each implant during manufacture, theinitial pulse width for the fixed resistor channel will be known. Fromstatistical data obtained about the behavior of the ICs under radiationexposure (data similar to FIGS. 17A and 17B), the slope of the curvewill be known. Therefore, real-time measurements from the fixed resistorchannel can be compensated to account for the variation based on thereference fixed resistor and known calibration data to give an accurateindication of the radiation exposure history for the implant. Using thistotal exposure computation, the temperature reading from the thermistorchannels can be corrected mathematically to give accurate temperaturereading at any radiation exposure level. That is, radiation damage orexposure can cause IC drift, and temperature drift. This is compared tothree parameters: a known fixed resistor value which is constant, atemperature sensor value which varies only in response to temperature,and the IC which is affected by both (thermal and radiation). Use of thecalibration data established at setup (or in the factory) can calibratethe signal data based on the number of known parameters to determine theradiation based drift and adjust for same. This drift is correctable asthe dose of radiation is well within the drift adjustment as indicatedby the FIGS. 17 and 18. In operation, a computer means cancomputationally perform the correction based on the data it receivesfrom one or more fixed resistors.

Accordingly, it is preferred that at least one fixed resistor 125R beused in the operating circuitry of the sensor, and preferably aplurality of fixed resistors. FIG. 14B illustrates one fixed resistorchannel (one reference) and four active monitoring channels. In oneembodiment, the sensor unit 50 includes three resistors, one issubstantially invariant with temperature or radiation (the fixedresistor 125R), one changes with temperature (a thermistor), and onechanges with both temperature and radiation (typically the MOSFET's inthe chip have a resistance that changes with both). The thermistor hasan associated measured temperature dependent curve. The fixed resistorcan be used to correct the bias on the MOSFET'S (adjust or compensatefor their drift due to radiation exposure/damage). The computer can givea corrected reading such as a temperature profile.

During normal operating conditions, the implant device may be powereddown when radiation (high dose-rate gamma, thermal RF and microwave, orultrasound) is applied to the patient. A series of tests were conductedto determine the effects of exposure/energy challenge events fromexemplary treatment sources at Triangle Radiation Oncology Services(TROS). First, 8 MHz energy (Thermotron RF-8) at levels well above thoseused in treating patients was applied to the device in both itspowered-down and powered-up states. Next, the tests were repeated forgamma radiation using a Varian Clinac 4/80. Finally, the tests wereagain repeated using microwave (915 MHz) energy from a Clini Thermsurface tumor heating instrument. In all cases, the device was notdamaged by the energy challenge tests, and continued to make accuratetemperature measurements after the conclusion of the tests. All testwere conducted on the same implant device so that the cumulative effectof the challenge tests were negative.

In order to assess biosurvivability and biocompatibility, several mockimplant devices were fabricated using materials that are similar to thepreferred embodiments of the sensor units described above. The overallscheme for fabricating a mock implant is highlighted in FIG. 5. Thesubstrate 120 can be fabricated using five-mil flexible Kapton®polyimide material covered by a 25 micron copper layer. The metal layer122 is patterned using photolithography into the wiring harness for asimple oscillator circuit. Next, an insulating layer of polyimide can bedeposited and patterned to open conducting vias to the metal traces.Then surface mount electrical components 125 are placed and soldered tothe substrate. Next, a thermistor 51 is connected to the end branch ofthe implant substrate as shown in FIG. 5. Then a coil of antenna wire 58is mounted with the IC and/or SMT components 125 as illustrated in thefigure. Finally, a lithium coin-shaped battery 52 is attached to thesubstrate 120. The battery 52 is first affixed to the substrate in theposition shown in FIG. 5. The end flap 129 (the circle that contains thesecond battery connection) is then folded over the battery and attachedusing conducting silver epoxy. The entire device is then encapsulated ina biocompatible material such as a thin layer of silastic and/ormedical-grade silicone to protect it from the biological environmentduring implant.

Additional features can also be included in sensor units 50, 50′, 50″,50′″ based upon the specification of the user interface. For example,the ability to turn the battery on and off with an externally applied RFsignal can be included in an IC (chip) design. Another feature can bethe inclusion of pH sensor interface electronics. The pH sensors willpreferably be implemented on a biocompatible, flexible substrate such asthe Kapton® substrate shown in FIG. 10A (Cosofret, 1995). This design iscompatible with the Kapton® substrate shown in FIG. 5.

In one preferred embodiment, the present invention employsselfcalibrating oxygen, pH, or combination oxygen/pH sensors. Theoperating principle of the in situ, in vivo self-calibrating chronicallyimplanted sensor units 200, 201, 300 is based on water electrolysis atnoble metal electrodes as shown in FIGS. 20 and 22. Oxygen or hydrogencan be evolved by the electrolysis of water by applying a currentthrough a generating electrode (“GE”) 227 and counter-generatingelectrode (“GE′”) 227′ for a certain period. Accumulation of thesedissolved gas molecules at the GE 227, in turn, rapidly establishes amicroenvironment of oxygen saturation or hydrogen saturation in closeproximity to the microsensor. A two-point calibration procedure for theoxygen sensor unit 200 can then be performed, with the high pointcalibration being established in an oxygen-saturated phase, and the lowpoint calibration in an oxygen-depleted phase that is produced bysaturating the microenvironment with hydrogen. These transientperturbations of the microenvironment are expected to equilibraterapidly with the surrounding medium (tissue). With this in situ, in vivoself-calibration sensor units 200, 201, 300 periodic sensor calibrationcan be performed to check the operability and biosurvivability of achronically implanted device.

It is preferred that the self-calibrating sensor units 200, 201, 300 beconfigured with the following operational and physical specifications:

(1) Dynamic range:

(a) 0-760 mm Hg with at least 10 mm Hg resolution (for oxygen tension)and/or

(b) pH 5.0-8.0 with pH resolution of about 0.1;

(2) Concurrent operation during hyperthermia treatment sessions; and

(3) Minimum 4-6 week (preferably 6 week or 1.5 month) period ofoperation and more preferably at least a 3 month period of operation.

The water electrolysis method can be extended to perform a one point, insitu, in vivo calibration of an implanted pH sensor unit 201 (FIG. 10B)as well. A micro pH sensor unit 201 that is surrounded by a generatingelectrode will experience a titrating pH microenvironment during waterelectrolysis. If one repeatedly drives the electrolysis current forwardand backward through the generating electrode, the highest slope in thetime response of the pH sensor will occur at the moment of neutral pH(pH 7.0). Thus, a one-point calibration at neutral pH can be performedduring water electrolysis by checking the first derivative of sensorresponse during titration. The functionality of similar pH titratingmicrodevices has been demonstrated for a pH-static enzyme sensor orbuffer capacity sensor (Olthuis, 1992). This prior work stronglysupports the feasibility of one point pH calibration as an option intumor monitoring applications.

Previously, polarographic micro-oxygen sensors were fabricated onflexible Kapton® material. The basic electrochemical three-electrodecell configuration shown in FIG. 21 was adopted to avoid current flowand minimize surface material consumption in a micro-referenceelectrode. All electrodes were designed to be geometrically symmetric toassure diffusional mass transport of electrochemical species in allradial directions.

Two different designs were considered—one with rectangular bands andanother with concentric circles. The design with concentric circles gavebetter performance, which can be explained theoretically. The noise atan electrode-electrolyte interface is generated by two sources(Lambrechts, 1992)—white noise and 1/f noise. A lower form factor forthe electrode (the circumference to surface area ratio) results in alower white noise level, which implies that the noise generated bycircular electrode is lower than that by a band electrode with the samegeometric area. The 1/f noise is inversely proportional to the electrodearea. Also, magnitude of current output is proportional to the electrodearea. This means that current output level and 1/f noise limits thescaling of amperometric sensors to extreme small size for tissue oxygenmeasurements.

The layout for both configurations were performed using 20, 10, and 5micron line widths. FIG. 21 is a photograph of the fabricated prototypeoxygen sensor 200 (concentric configuration). All noble metal electrodeswere made of gold, the material that has been shown to possess the beststability when used as an oxygen catalyzer (Hoare, 1984).

Turning now to the function of each concentric circle shown in FIG. 21,the middle electrode serves as a working electrode (“WE”) 225 at whichdissolved oxygen molecules are electrochemically reduced. The GE 227 iswrapped around the working electrode; this configuration will establishoxygen-saturated or hydrogensaturated microenvironments duringself-calibration cycles. Proceeding from inside to outside, the nextconcentric circle is used as the reference electrode (“RE”) 229. Theoutermost electrode in FIG. 21 is the counter electrode (“CE”) 231 ofthis three-electrode cell. It is placed as far as possible from the WE225 to eliminate electrochemical interference at the WE of byproductsgenerated at the CE 231. The GE′ 227′ (not shown) is also locatedremotely from the WE 225 for this same reason. the past, pH sensors havealso been fabricated on flexible substrates (Cosfret, 1995). FIG. 10Aillustrates a pH sensor structure containing a p-HEMA central dome overa Ag/AgCl electrode. The final fabrication step is the deposition of theouter polymeric membrane containing the pH ionophore. These sensors haveperformed accurately in preliminary tests in vivo in blood for up totwo. months. The size of these potentiometric sensors are preferablyminimized to improve their capability for resolving spatial gradients.Further size reduction of the pH sensors shown in FIG. 10A may belimited by the manual deposition of the polymeric membrane solution,weaker adhesion to the substrate and high impedance, as the membranecontact area is diminished. Another drawback imposed by the use ofpolymeric membranes is the potential for leakage and degradation ofmembrane's plasticizer and ionophore for long-term operation. Morerecently, work has been done to miniaturize pH sensors by replacing thepolymeric membrane by a solid state analogue. The best alternativeidentified to date is iridium oxide which has been shown to possessexcellent pH-sensing capability and can be deposited on the sensorsurface using a simple electroplating method (Marzouk, 1998). This newstructure is shown in FIG. 10B.

Self-calibrating O₂ sensors, such as shown in FIG. 21, have beenfabricated by facilities in BMMSL (Biomedical Microsensors laboratory)at North Carolina State University. Tables 2 and 3 summarize a preferredfabrication process of oxygen sensors 200 and pH sensors 201,respectively.

TABLE 2 Oxygen Sensor Process Process Steps Process Details Substrate3-mil Kapton ® VN selection Cleaning Organic solvent cleaning anddehydration Metal Deposition DC Magnetron sputtering 200 Å Cr followedby 2000 Å Au Photolithography Spin coated 1.3 μm Shipley 1813photoresist,. Contact exposure with Tamarack Alignment and ExposureSystem. (Exposure energy optimized for 5-μm linewidth.) Metal EtchingWet chemical etching Cleaning Organic solvent cleaning and dehydrationPolyimide process Spin coated 2-μm Pyralin PI-2721 photosensitivepolyimide. Contact exposure with Tamarack system. Spin development andthermal curing in atmosphere

TABLE 3 pH Sensor Process Process Steps Process Details Substrateselection 5-mil Kapton ® VN Cleaning Organic solvent cleaning anddehydration Metal Deposition DC Magnetron sputtenng 200 Å Ti followed by2000 Å Pt with shadowmask Cleaning Organic solvent clean and dehydrationP2Y olyimide process Spin coated 5-μm Pyralin PI-2721 photosensitivepolyimide. Contact exposure with Tamarack system. Spin development andthermal curing in atmosphere Electrodeposition Electroplate IrO_(x)according to the established method (Marzouk, 1998)

Another preferred embodiment of an in situ sensor unit is shown in FIG.22 as a combination pH/O₂ sensor unit 300. As the combination sensorunit 300 assumes smaller feature sizes, the area of the generatingelectrode and, thus, its current carrying capacity, is reduced. Asmaller structure will also enable the new sensors to be employed inlinear arrays for gradient measurements. The microenvironment of thesmaller sensor may require less oxygen to become saturated. Once the GE327 has established a saturated microenvironment, these conditions willbe dissipated rapidly unless structural measures are taken to delayoxygen and pH equilibration. Hence, the self-calibrating design canemploy a recessed structure (a micropool) to sustain the saturatedmicroenvironment for a limited sensor calibration period. Thus, a3-dimensional micropool can be configured by using layers ofphotosensitive polymers to build walls to confine the working andgenerating electrodes 325, 327. The volume of the micropool can alsodetermine the overall sensor unit 300 performance and the time periodneeded for calibration. A near optimum design can be determined byiterating several of the design parameters in various fabrication runs.It is noted that some surface degradation and adhesion problems at thepolyimide/metal interface at the electrode edges were observed duringprototype experiments (at current densities exceeding 10 mA/cm²).

The conventional Clark oxygen sensor contains a reference electrode(anode) and a working electrode (cathode) located in the samecompartment encapsulated by hydrophobic, electrically non-conductingmembrane. In contrast, the instant design separates the RE 329 and WE325 to allow a space for the GE 227 (positioned therebetween and placedto control the micro environment of the WE 225) as illustrated in FIGS.21 and 22. This new arrangement is in contrast to the conventional Clarksensor, which may not be suitable for long-term implantation due to therisk of membrane rupture and the subsequent degradation of the sensor'sinternal filling solution. In this design, the separated RE and WE areelectrically coupled via a hydrophilic permeable membrane and tissuefluids. This separated configuration for the RE and WE can causedifficulties due to increased solution resistance when the anode is veryfar from the cathode. However, the 3-electrode system reduces thiseffect. Another difficulty can be introduced by WE surface contaminationdue to direct contact with components of tissue fluid that penetrate thepermeable membrane. As such, it is preferred that the electrode materialused be selected to reduce this behavior. For example, it hasdemonstrated (Holmstrom, 1998) that a bare gold electrode, implanted upto 4 years for oxygen monitoring, absorbed less blood proteins than aglassy carbon electrode, and no adverse tissue reactions were observed.

To minimize any electrostatic coupling between the 3-electrode cell andgenerating current source, the operation of the sensor 300 is preferablydivided into separate calibration and measurement modes. To simplify thedevice structure, the counter electrode (CE) will preferably serve adual as the counter-generating electrode (GE′) of generating source.Thus, a single electrode that can be switched between the twooperational modes and can serve both functions.

Preferably, to reduce the feature size and reliably form same duringfabrication, a silicon wafer-supported flexible substrate process isused to reduce thermal expansions and surface roughness distortions. Inthis fabrication process, polyimide (DuPont P12723) is spin-cast to athickness of about 25 μm onto a thermal oxide coated silicon wafer.After all sensor processing steps have been completed, the wafer issoaked in a dilute H.F. solution. The thermal oxide is etched away andthereby releasing the flexible polyimide substrate and its sensorstructures.

A recessed sensor structure can also be implemented using photosensitivepolymer materials. Thicknesses of up to 30 μm can be obtained with a2-step spincoating procedure. Other materials are also available forthis purpose. For example, a dry film (DuPont Pyralux or Vacrel whichhave thicknesses of 25 to 100 μm) can be laminated over the device usinga thermal vacuum process. The highest aspect ratio (depth:width) for themicropool that can be fabricated using these laminated films istypically about 1:1. This ratio can be maintained for depths from 10 to100 μm.

Platinum is known as the best noble metal electrode for waterelectrolysis and is easily deposited and patterned usingmicrofabrication technology. In previous experiments with physiologicalsolutions containing rich chloride ions, surface chloridation of goldgenerating electrodes was observed during the positive potential regionof water electrolysis. This problem should be alleviated by replacingthe gold generating and counter electrodes with platinum. Forsimplicity, in photo-processing steps, a titanium platinum layer willserve as both electrodes and wiring leads. To generate the otherelectrode surfaces, gold can be electroplated (for the workingelectrode) and silver (for the reference electrode) onto the platinumlayer. For the pH sensor, iridium oxide will also be plated. The devicesare designed so that the electroplating steps are self-aligning, and noadditional photopatterning will be required. These procedures havealready been established (Marzouk, 1998). Currently, the preferredpermeable membrane material is p-HEMA covered with polystyrene orcollodion (Kreuzer, 1980).

The overall process sequence is shown in FIGS. 23A-23C. Platinum isdeposited by sputtering and then patterned by photolithography. Next, athin layer of polyimide is spin-coated and patterned to define thevarious electrode areas and to insulate the wiring conductors. Then athick polymer micropool is defined around working electrode andreference electrode area by a lamination process. Next, gold (as theoxygen catalyzer) or iridium oxide (as the pH-sensitive layer) will beelectroplated, followed the plating and chloridation of silver (as theRE). Finally, a permeable membrane is cast by micromanipulation andcured. In operation, it should be noted that with continuous polarizingvoltage during oxygen sensor operation, one disadvantage can be arelatively large oxygen consumption and power consumption as well asaging effect. This power consumption is preferably reduced to provideelectrode stability. Thus, intermittent or periodic measurement arepreferably instituted with a potential step. Necessary calibrationparameters such as current density and duration can be determined forproper calibration of periodic measurements.

The present invention is explained further in the following examples.These examples are for illustrative purposes only, and are not to beconstrued as limiting of the invention.

EXAMPLE

A patient presents with an unresectable lung cancer (adenocarcinoma orsquamous cell). The conventional accepted treatment is a combination ofradiation and chemotherapy. The radiation is given everyday, Mondaythrough Friday, and the chemotherapy (taxol and cisplatin) areadministered either once a week in low doses or every three weeks inhigher doses. All patients are treated in substantially the same mannerand the expected response rate is between 50-75%. Therapy is notindividualized despite the fact that it is known that oxygen levels, pH,and particularly, cell doubling times, may vary widely between patients.

The availability of the methods, systems, and implantable sensors of thepresent invention which are configured to monitor pH, oxygen, andradiation, now offer a more customized approach to therapy. The sensorscan be positioned in situ in the tumor at different penetration depthsor across different regions of the tumor to provide regional specificinformation. Specific values or oxygen, pH, and cell proliferation canbe established either prior to initiation of treatment by a predictivestatistical norm in an established data base, or during initialtreatment to define relative values, the specific values are identifiedas either a “go” for treatment or a “no go” for treatment to determinewhen and if a treatment should be commenced. A monitoring algorithm canbe used to quantify important values of variables and an affirmativeattempt can be made to correct each variable to reach or approximate thedesired specific levels at treatment. For example, to manipulate thetumor to achieve oxygenation of about 50-52 mm Hg over a substantialvolume of the tumor, as well as to exhibit a lower tumor pH of about6.8, and to stimulate or identify and deliver during periods ofincreased cell proliferation.

Following the initial dose of radiation or chemotherapy, each variablewill be monitored to determine an appropriate time (associated with afavorable treatment period) to deliver the next dose of radiation and/orchemotherapy. Preferably, each patient is monitored at least four timeseach day following treatment to establish a specific response patternfor an individual patient. Utilizing this ongoing, periodic monitoringapproach can allow delivery of any cytotoxic agent in a more precise andfavorable manner and/or to withhold treatment during tumor treatmentresistant periods. It is preferably to treat when all variables indicatethat the tumor is vulnerable such as when there is an indication of highoxygenation level, low pH, and increased cell proliferation. It thevariables do not synchronize to indicate a favorable index at the sametime, then a statistical regression analysis can be identified to definean appropriate treatment time. It will be appreciated that in additionto radiation and chemotherapy, hyperthermia and/or other treatments canbe incorporated into the treatment protocol, especially in tumorsexhibiting a high hypoxic fraction. This can allow for increased cellkill, after which the kinetics of the tumor will change and allow formore precise delivery of the radiation and/or chemotherapy. Thus, theindividualized treatment will allow the delivery of cytotoxic agents ata favorable treatment time to achieve increased tumor cell kill, andthereby increase the response of the tumor to the treatment. In thisexample, when a satisfactory response has been obtained, the tumor canbe removed.

In summary, the individualization of therapy can now be instituted basedon obtaining information on the dynamic changes within each individualpatient's tumor. This information should lead to increase tumor cellkill, increased survival and decreased morbidity. This should translateinto a decrease in the cost of treating patients by a decrease inmorbidity and therefore less hospitalization; increase the effectivenessof cytotoxic agents by allowing for delivery of increased dose or even adecrease in the dose through more efficient timing of delivery of thecytotoxic. The present invention can monitor and provide information ondynamic changes occurring within a tumor.

The foregoing is illustrative of the present invention and is not to beconstrued as limiting thereof. Although a few exemplary embodiments ofthis invention have been described, those skilled in the art willreadily appreciate that many modifications are possible in the exemplaryembodiments without materially departing from the novel teachings andadvantages of this invention. Accordingly, all such modifications areintended to be included within the scope of this invention as defined inthe claims. In the claims, means-plus-function clause are intended tocover the structures described herein as performing the recited functionand not only structural equivalents but also equivalent structures.Therefore, it is to be understood that the foregoing is illustrative ofthe present invention and is not to be construed as limited to thespecific embodiments disclosed, and that modifications to the disclosedembodiments, as well as other embodiments, are intended to be includedwithin the scope of the appended claims. The invention is defined by thefollowing claims, with equivalents of the claims to be included therein.

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That which is claimed is:
 1. A method of monitoring and evaluating thestatus of a tumor undergoing treatment, comprising the steps of: (a)monitoring in vivo at least one physiological parameter associated witha tumor in a subject undergoing treatment with an in situ sensor unit;(b) transmitting data associated with the at least one monitoredphysiological parameter from the in situ positioned sensor unit to areceiver located external to the subject; (c) analyzing the transmitteddata to determine a condition of the tumor; (d) repeating steps (a),(b), and (c) periodically at a plurality of sequential points in time;and (e) evaluating a tumor treatment strategy comprising at least oneof: identifying a favorable or unfavorable tumor treatment time foradministration of at least one of a radiation, drug, and chemicaltherapy; evaluating the efficacy of at least one of therapeuticradiation, drug, and chemical treatment on the tumor; determining theamount of radiation delivered in vivo to the tumor site; monitoringradiolabeled drug uptake at the tumor site; and analyzing thetransmitted data to monitor the influence of at least one of a thermal,chemical, or radiation therapy on the tumor based on data transferredbefore, during and after the therapy.
 2. A method according to claim 1,wherein the at least one monitored physiological parameter includes thetemperature proximate the tumor site and at least one of the pH at thetumor site, the level of oxygenation at the tumor site, cellproliferation at the tumor site, and the amount of radiation exposure atthe tumor site, and wherein said transmitting and analyzing steps arerepeated sufficiently to track variation in the at least one of themonitored parameters and thereby assess the behavior of the tumor overtime.
 3. A method according to claim 1, wherein said monitoring stepmonitors a plurality of tumor physiological parameters, and wherein saidanalyzing step defines a plurality of predetermined test conditions,wherein at least one test condition associated with identifying afavorable treatment time and at least one test condition associated withidentifying an unfavorable treatment time, and wherein said methodfurther comprises the step of alerting a clinician as to when thetransmitted data satisfies one of said test conditions which identifieswhen a favorable unfavorable treatment window for delivering asubsequent active treatment to the tumor is identified.
 4. A methodaccording to claim 3, wherein said favorable treatment test conditionincludes test criteria corresponding to the identification of a tumorsusceptibility or vulnerability phase.
 5. A method according to claim 2,wherein said transmitting step comprises transmitting data from anon-clinical site of a patient to a remote clinical site therebyallowing remote dynamic monitoring of the at least one physiologicalparameter.
 6. A method according to claim 1, wherein steps (a) and (b)are repeated temporally proximate to an active treatment delivery of atleast one of a radiation therapy and a chemotherapy to provide real-timeinformation regarding the tumor and the appropriateness of proceedingwith the active treatment at that time.
 7. A method according to claim1, wherein steps (a) and (b) are repeated during an active therapeuticcytotoxic chemical treatment delivery to provide real-time informationto a physician to allow therapeutic treatment decisions based on thesubstantially real time monitored tumor parameters.
 8. A methodaccording to claim 1, wherein a therapeutic oncology treatment protocolis adjusted based on tumor information provided by the monitored in vivophysiological parameter of the tumor particular to the subject.
 9. Amethod according to claim 1, wherein said repeating step is carried outat least once every 24 hours.
 10. A method according to claim 1, whereinthe repeating step is carried out at varying time intervals responsiveto the progression or stage of treatment and responsive to detectedrelative changes in the monitored parameters.
 11. A method according toclaim 1, further comprising electronically storing a series oftemporally related data measurements to dynamically monitor thevariation in the at least one monitored physiological parameterovertime.
 12. A method according to claim 1, wherein the tumor is one ofcarcinoma and scarcoma.
 13. A method according to claim 1, wherein thetumor is a solid mass.
 14. A method according to claim 1, furthercomprising the step of positioning at least one sensor unit configuredto monitor a plurality of physiological parameters into a subject suchthat it is positioned in in situ in vivo contact with a target tumor,wherein the positioned sensor unit has a service life of at least about4-10 weeks.
 15. A method according to claim 1, wherein said monitoringstep is performed by a sensor unit with a plurality of sensor elementspositioned in situ, and wherein said sensor unit is positioned in thesubject by at least one of implanting and injecting the sensor unit suchthat at least one of the sensor elements contacts the tumor.
 16. Amethod according to claim 14, wherein said positioning step comprisesinjecting multiple discrete dependent sensor units into the subject suchthat they contact the target tumor and further comprises implanting asatellite sensor unit in wireless electrical communication with saiddependent sensor units into the subject such that the satellite sensoris positioned proximate to said dependent sensor units.
 17. A methodaccording to claim 1, wherein said evaluating step includes at least oneof determining the efficacy of the treatment and identifying asubsequent active favorable treatment window.
 18. A method according toclaim 17, wherein the subject has multiple tumors, and wherein saidmethod further comprises positioning a first sensor unit in situ tocontact a first tumor and positioning a second sensor unit in situproximate to a second tumor different from the first tumor.
 19. A methodaccording to claim 15, wherein at least one of said sensor elements isconfigured to monitor the toxic effects of treatment on normal celltissue proximate to the tumor.
 20. A method according to claim 1, saidmethod further comprising the step of monitoring at least one parameterassociated with normal cells proximate to the tumor.
 21. A methodaccording to claim 20, wherein said normal cell monitoring parameter ispH and wherein said at least one monitored tumor parameter is pH.
 22. Amethod according to claim 21, wherein said analyzing step compares thenormal cell pH with the tumor pH and wherein said evaluating stepincludes reviewing the relative difference between the two pH parametersto establish a treatment strategy.
 23. A method according to claim 1,wherein said monitoring step monitors a plurality of different tumorphysiological parameters.
 24. A method according to claim 23, whereinsaid plurality of different tumor physiological parameters comprises pH,oxygenation, temperature, and quantification of the amount of radiationtherein.
 25. A method according to claim 23, wherein said monitoringstep comprises detecting a period of increased cell proliferation and anincreased level of oxygenation.
 26. A method according to claim 15,wherein said multiple sensors have an extended clinically useful life ofabout at least 4-6 weeks.
 27. A method according to claim 23, whereinsaid monitoring step monitors at least two of temperature proximate thetumor site, oxygenation level proximate the tumor site, deliveredradiation proximate the tumor site, and pH level proximate the tumorsite, and wherein said analyzing step predetermined test criteriaevaluates the presence of at least one of an elevated oxygenation level,an elevated radiation level, and a decreased pH level.
 28. A methodaccording to claim 1, wherein said evaluating step comprises the stepsof tracking the results of the monitored data over a period of time andcomparing the transmitted data against a predictive model to determinewhen a planned therapeutic tumor treatment indicates an adjustment isdesired based on deviation of the tumor's response to the deliveredtherapy as measured against a population norm.
 29. A method according toclaim 1, wherein said predetermined test criteria includes absolute andrelative test conditions.
 30. A method according to claim 1, whereinsaid analyzing step identifies the amount of time elapsed from the timeof the last active radiation or chemotherapy treatment.
 31. A methodaccording to claim 2, wherein said analyzing step tracks a dynamichistory of at least two of the monitored parameters over time.
 32. Amethod according to claim 20, further comprising administering one of acytotoxic agent and radiation to the subject, and assessing the toxiceffects on normal cell tissue proximate to the target tumor site.
 33. Amethod according to claim 1, said method further comprising establishinga known active treatment date and known active treatment dose, whereinsaid monitoring step monitors the amount of treatment dose received atthe tumor, and wherein said analyzing step compares the received dosewith the known dose and identifies a discrepancy from the delivered doseto the measured dose to thereby confirm the efficacy of a targetedtreatment dose.
 34. A method according to claim 15, wherein said sensorunit includes sensor electronics, and wherein said method furthercomprises the step of adjusting the transmitted data to account fordeviations in the data attributed to the sensor unit's exposure to atleast one of radiation and temperature.
 35. A method according to claim3, wherein the predetermined test criteria identifies the presence of aclustering of test conditions including the presence of an elevatedoxygenation level and a period of cell proliferation measuredcorresponding to an elevated radiation level at the tumor.
 36. A methodaccording to claim 1, wherein said evaluating step includes adjusting achemical or radiation treatment dose, delaying or advancing the nextactive treatment delivery of one of a chemical, radiation, and thermaltherapy, or altering a selected treatment therapy type of one ofchemical, radiation, or thermal to a different one.
 37. A methodaccording to claim 3, wherein said method further comprisesautomatically scheduling an active treatment session or evaluationappointment at a clinic.
 38. A method according to claim 1, wherein saidmonitoring step is carried out remotely over at least one of a telephoneline, fiber optic line, cable line, a computer modem, an internethook-up, and other wireless communication mode.
 39. A method accordingto claim 1, wherein said monitoring step is carried out via at least onesensor unit having a plurality of in situ sensor elements having aservice life of at least about 4-10 weeks, and wherein said methodfurther comprises the step of locally transmitting data associated withthe at least one monitored physiological parameter representative of aphysiological condition associated with the tumor thereby providingsubstantially real-time information regarding the condition of thetumor.
 40. A method according to claim 39, wherein said localtransmitting step is performed before an active therapy session todetermine the suitability of delivering an active treatment.
 41. Amethod according to claim 39, wherein said local transmitting step isperformed during an active radiation, chemical, or thermal therapysession to control at least one of the amount, rate, or length of anactive treatment session.
 42. A tumor monitoring system for identifyingenhanced active cancer treatment windows, comprising: at least oneimplantable sensor unit comprising a plurality of sensor elements andassociated sensor electronics, wherein a plurality of said plurality ofsensor elements are configured for in vivo in situ contact with acancerous tumor in a subject undergoing treatment for cancer, andwherein said sensor elements are configured to detect a plurality ofdifferent parameters associated with the tumor and wirelessly transmitdata associated with the detected parameters, wherein said plurality ofdifferent parameters includes at least two of the amount of radiationexposure at the tumor site, extracellular pH of the tumor, pH of normaltissue, tumor cell oxygenation, tumor cell proliferation andtemperature; a remote receiver in wireless communication with said atleast one sensor, said receiver configured to receive the transmitteddata, wherein said receiver is spatially separate from said at least onesensor and positioned external to the subject; and a processor havingcomputer readable program code for analyzing the transmitted data toidentify the presence or absence of a favorable cancer treatmentcondition.
 43. A tumor monitoring system according to claim 42, furthercomprising computer readable program code means for reviewing andadjusting the received transmitted data to correct for variations in thesignal data attributed to environmental exposure of the sensor unit orsensors elements held in the subject.
 44. A tumor monitoring systemaccording to claim 42, wherein, in position, said plurality of sensorelements are configured to reside at different locations on and withinthe tumor, and wherein at least one of said plurality of sensor elementsis configured to contact normal tissue cells proximate to the tumor. 45.A tumor monitoring system according to claim 42, wherein said remoteunit is configured to be worn by the subject, and wherein said remotereceiver further comprises a remote interface to allow a user totransmit data from a physically remote non-clinical site to a centralprocessing unit at a clinical site during a non-emission cancertreatment period.
 46. A tumor monitoring system according to claim 42,wherein said sensor unit is configured as a cylindrically shaped bodyhaving opposing first and second ends, and wherein said sensor unitincludes an inductively coupled power source, wherein said sensor issized to have a length which is less than about 0.5 inches (1.27 cm) andis configured to be injectable via a trochar into the subject such thatat least one of said first and second ends contacts a tumor within amammalian body, and wherein said at least one sensor unit has animplanted service life of at least about 4-10 weeks.
 47. A tumormonitoring system according to claim 42, wherein said sensor unitcomprises operating electronics positioned within a first body portionand a plurality of flexible arms extending outwardly therefrom, each ofsaid arms having distal portions containing at least one sensor elementthereon and having at least one signal path between said operatingelectronics in said first body portion to each of said sensor elementsin each of said arms.
 48. A tumor monitoring system according to claim42, wherein said sensor unit includes an inductively coupled powersource, and wherein at least one of said arms includes a plurality ofsensor elements.
 49. A tumor monitoring system according to claim 42,wherein said arms are configured with an anchor portion to positionallyattach to a desired portion of the tumor.
 50. A tumor monitoring systemaccording to claim 42, wherein said sensor elements include at least onepH sensor element, at least one oxygen sensor element, at least onetemperature sensor element, and at least one radiation sensor element.51. A tumor monitoring system according to claim 42, wherein said atleast one sensor unit comprises a plurality of sensor elements isconfigured as an implantable satellite sensor unit and an associatedplurality of injectable discrete dependent sensor units, wherein each ofsaid discrete dependent sensor units have at least one sensor elementthereon, and wherein said plurality of discrete dependent sensor unitsare in wireless communication with said satellite sensor unit.
 52. Atumor monitoring system according to claim 42, wherein said at least onesensor unit is a plurality of sensor units, and wherein each sensor unitincludes a unique identifier to allow transmitted data to be correlatedto the appropriate in situ sensor unit position.
 53. A tumor monitoringsystem according to claim 42, wherein said remote receiver is portableand wearable by the patient so as to be held proximate thereto.
 54. Acomputer program product for monitoring and analyzing the condition of atumor in a patient undergoing cancer treatment, the computer programproduct comprising: a computer readable storage medium having computerreadable program code means embodied in said medium, saidcomputer-readable program code means comprising: computer readableprogram code means for commencing a first wireless data transmissionfrom an in situ wireless sensor with at least one sensor elementpositioned in a subject proximate to a tumor site undergoing treatmentfor cancer, the data transmission including data corresponding to theoutput of the at least one sensor element; computer readable programcode means for commencing a second wireless data transmission from thein situ sensor temporally separate from the first wireless datatransmission; computer readable program code means for trackingvariation between the first and second data transmissions to provide adynamic behavioral model of the tumor's response to the treatment;computer readable program code for analyzing the transmitted data toidentify at least one favorable cancer treatment opportunity; computerreadable program code means for evaluating at least one of (a) theamount of radiation exposure delivered to the tumor site from a cancerradiation treatment session, (b) cell proliferation associated with thetumor, (c) the response of normal tissue proximate the tumor site to thecancer treatment; (d) the value of at least one physiological orbiological parameter of the tumor to evaluate efficacy of a cytotoxic ortargeted drug or chemical treatment or to confirm delivery of thecytotoxic or targeted drug or chemical treatment to the tumor site, (e)a variation in the value of a physiological or biological parameter ofthe tumor from a predictive model, (f) the presence of an unfavorablecancer treatment period, and (g) the value of at least one physiologicalor biological parameter of the tumor to identify a receptiveness for aparticular cancer therapy type.
 55. A computer program product accordingto claim 54, wherein said computer readable program code means forevaluating includes computer program code means for evaluating theefficacy of the cancer treatment by comparing the value of at least onepredetermined physiological or biological parameter to a correspondingpredetermined value established for each of the at least onephysiological or biological parameters.
 56. A computer program productaccording to claim 54, wherein said computer readable program code meansfor evaluating includes computer program code means for evaluating theefficacy of the cancer treatment by comparing the value of at least onepredetermined physiological or biological parameter to a correspondingrelative change in the monitored at least one physiological orbiological parameters, over time.
 57. A computer program productaccording to claim 54, further comprising computer readable program codemeans for commencing ongoing periodic data transmissions over apredetermined time period, the predetermined time period including timeaway from a clinical treatment site, and computer readable program codemeans for analyzing the periodic data transmissions to identify afavorable active cancer treatment opportunity.
 58. A computer programproduct according to claim 54, further comprising computer readableprogram code means for initiating a subsequent data transmissiontemporally proximate to a planned treatment time to thereby provide realtime information for therapeutic decisions regarding the condition ofthe tumor in a manner which can estimate the likelihood of success of aplanned treatment strategy.
 59. A computer program product according toclaim 58, further comprising computer readable program code means forinitiating a subsequent data transmission during an active treatmentsession to thereby provide real time information for therapeuticdecisions regarding the treatment session itself.
 60. A computer programproduct according to claim 59, further comprising a computer readableprogram code means for controlling the delivery of the treatment itselfcorresponding to a change in the one or more monitored physiologicalparameters during the treatment session.
 61. A computer program productaccording to claim 54, further comprising computer readable program codemeans for remotely directing the transmission of data from anon-clinical site to a clinical or data processing site remote from thenon-clinical site for offsite evaluation.
 62. A computer program productaccording to claim 57, wherein said ongoing periodic data transmissionsmonitors the at least one physiological parameter at least at sequentialsemi-continuous time intervals, and wherein said computer programproduct comprises computer readable program code means for storing thesemi-continuously monitored data transmissions and then subsequentlytransmitting the stored data transmissions as a bulk update to aclinical site.
 63. A computer program product according to claim 54,wherein said computer program code means evaluates a plurality of saiditems (a) through (e).
 64. A computer program product according to claim63, wherein said computer program code means evaluates at least three ofsaid items (a) through (e).
 65. A computer program product according toclaim 64, wherein said computer program code means evaluates all of saiditems (a) through (e).
 66. A computer program product according to claim63, wherein said computer readable program code means for evaluating thevalue of at least one physiological or biological parameter of the tumorto evaluate efficacy of a cytotoxic or drug or chemical treatment or toconfirm delivery of the cytotoxic or drug or chemical treatment to thetumor site comprises comparing the pH of the subject's normal tissue tothe extracellular pH of the tumor tissue.
 67. A computer program productaccording to claim 63, wherein said computer readable program code meansfor evaluating the value of at least one physiological or biologicalparameter of the tumor to evaluate efficacy of a Cytotoxic or drug orchemical treatment or to confirm delivery of the cytotoxic or drug orchemical treatment to the tumor site comprises comparing theextracellular pH of the subject's cancerous tumor tissue to apredetermined value before delivery of an active cancer treatment.
 68. Acomputer program product according to claim 63, wherein said computerreadable program code means for evaluating the amount of radiationexposure delivered to the tumor site during a cancer radiation treatmentsession confirms that the radiation level received at the tumor site isbetween about 3000-6000 cG.
 69. A computer program product according toclaim 63, wherein said computer readable program code means forevaluating a variation in the value of a physiological or biologicalparameter of the tumor from a predictive model compares thephysiological or biological values of the tumor to a statistical modelof values at corresponding periods of time into comparative treatmentregiments.
 70. A computer program product according to claim 63, whereinsaid computer readable program code means for evaluating the value of atleast one physiological or biological parameter of the tumor identifiesan unfavorable cancer treatment period associated with when the tumor ishypoxic.
 71. A computer program product according to claim 63, whereinsaid computer readable program code means for evaluating the value of atleast one physiological or biological parameter of the tumor identifiesa favorable cancer treatment period associated with when the tumor is inan active cell proliferation phase.
 72. A computer program productaccording to claim 63, wherein said computer readable program code meansfor evaluating the value of at least one physiological or biologicalparameter of the tumor to identify a receptiveness for a particularcancer therapy type identifies the extracellular pH level of the tumorfor assessing which drug to administer to the patient.